Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: ATF3 is a DNA-binding RNA polymerase II transcription factor. Reason: The bZIP domain, CRE/ATF-site binding, and extensive transcriptional regulation evidence support this as a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length ATF3. Reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that the ATF3 homodimer represses transcription. Supporting Evidence: PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific	IEA GO_REF:0000107	ACCEPT	Summary: ATF3 has direct DNA-binding transcription repressor activity. Reason: Full-length ATF3 represses ATF-site promoters and ATF3 homodimers repress transcription, making this a core molecular function of the canonical full-length protein. Supporting Evidence: PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IEA GO_REF:0000107	ACCEPT	Summary: ATF3 can act as a context-dependent RNA polymerase II transcriptional activator through heterodimers, splice isoforms, and specific target promoters. Reason: Although canonical full-length ATF3 is often a repressor, published evidence and the deep research synthesis support context-dependent activator activity in specific partner, promoter, and isoform contexts, including Jun/ATF3 promoter activation, ATF3-dependent EphA1 promoter activation, and delta-Zip relief of repression. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0008284 positive regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Positive regulation of cell population proliferation is reported in disease and stress contexts but is a broad downstream phenotype. Reason: The deep research and older isoform literature describe ATF3 roles in proliferation and cancer contexts, but this process is an indirect systems-level outcome of transcriptional regulation and should not be treated as core. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0010628 positive regulation of gene expression	IEA GO_REF:0000107	MODIFY	Summary: positive regulation of gene expression is directionally consistent with ATF3 biology but is less specific than existing ATF3 transcription-factor annotations. Reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory DNA binding. The current broad term is true but less informative than the more specific ATF3 terms already supported by IBA, UniProt, and primary literature. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: endoplasmic reticulum unfolded protein response is a supported stress-response context for ATF3 but not the core molecular function. Reason: ATF3 is induced downstream of ER stress and ISR/ATF4 signaling and regulates stress-response targets. These process terms are useful context, but the conserved core function remains nuclear transcriptional regulation rather than ER-stress sensing itself. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0034198 cellular response to amino acid starvation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: cellular response to amino acid starvation is a supported stress-response context for ATF3 but not the core molecular function. Reason: This IEA row is an orthology-transfer context from mouse Atf3, and amino acid starvation is one trigger of the integrated stress response. The reviewed human evidence supports ATF3 as a downstream ISR/eIF2alpha-ATF4 transcriptional effector, but the conserved core function remains nuclear transcriptional regulation rather than amino-acid starvation sensing itself. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara; the GOA row is an amino acid-starvation response annotation transferred from mouse Atf3. file:human/ATF3/ATF3-deep-research-falcon.md Amino acid starvation is interpreted here as an integrated stress response input; recent mechanistic work strengthens a unifying view of ATF3 as a stress-to-transcription coupling factor downstream of ISR/eIF2alpha-ATF4 signaling in multiple contexts.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000120	ACCEPT	Summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts, especially heterodimers and stress-response target promoters. Reason: ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters, ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization. This is real biology, but it should be interpreted together with ATF3 repressor annotations. Supporting Evidence: PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0070373 negative regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Negative regulation of the ERK1/ERK2 cascade is not a well-supported direct ATF3 function in the reviewed human evidence. Reason: This IEA transfer may reflect a downstream pathway effect in a specific ortholog/context. The ATF3 review evidence supports transcriptional regulation and stress-response coupling, but not direct negative regulation of ERK signaling as a core annotation. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0005515 protein binding	IPI PMID:10327051 The N-terminal transactivation domain of ATF2 is a target fo...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Same treatment applied to all other GO:0005515 IPI rows in this review. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:18255255 A protein-protein interaction network of transcription facto...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:19164757 ERAD inhibitors integrate ER stress with an epigenetic mecha...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:20102225 Identification of bZIP interaction partners of viral protein...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:25609649 Proteomic analyses reveal distinct chromatin-associated and ...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005515 protein binding	IPI PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment...	MARK AS OVER ANNOTATED	Summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but this term does not capture the informative function. Reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization annotations and transcription-factor complex annotations better represent the biologically meaningful interaction function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0042802 identical protein binding	IPI PMID:18255255 A protein-protein interaction network of transcription facto...	MODIFY	Summary: ATF3 homodimerization is well supported, but protein homodimerization activity is the more specific term. Reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is central to DNA recognition and regulatory output. GO:0042802 is valid but less specific than GO:0042803, which captures the same supported homodimerization activity more directly. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0042802 identical protein binding	IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov...	MODIFY	Summary: ATF3 homodimerization is well supported, but protein homodimerization activity is the more specific term. Reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is central to DNA recognition and regulatory output. GO:0042802 is valid but less specific than GO:0042803, which captures the same supported homodimerization activity more directly. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0003677 DNA binding	IEA GO_REF:0000120	MODIFY	Summary: DNA binding is directionally consistent with ATF3 biology but is less specific than existing ATF3 transcription-factor annotations. Reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory DNA binding. The current broad term is true but less informative than the more specific ATF3 terms already supported by IBA, UniProt, and primary literature. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000002	MODIFY	Summary: DNA-binding transcription factor activity is directionally consistent with ATF3 biology but is less specific than existing ATF3 transcription-factor annotations. Reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory DNA binding. The current broad term is true but less informative than the more specific ATF3 terms already supported by IBA, UniProt, and primary literature. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000120	MODIFY	Summary: regulation of DNA-templated transcription is directionally consistent with ATF3 biology but is less specific than existing ATF3 transcription-factor annotations. Reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory DNA binding. The current broad term is true but less informative than the more specific ATF3 terms already supported by IBA, UniProt, and primary literature. Proposed replacements: regulation of transcription by RNA polymerase II Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0006357 regulation of transcription by RNA polymerase II	IEA GO_REF:0000002	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:1990837 sequence-specific double-stranded DNA binding	IEA GO_REF:0000117	ACCEPT	Summary: sequence-specific double-stranded DNA binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005730 nucleolus	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Nucleolus localization is reported in immunofluorescence data but is not the primary site of ATF3 transcription-factor action. Reason: The core supported localization is nucleus/nucleoplasm/chromatin. Nucleolus may be a detected subnuclear localization, but the reviewed literature does not make it central to ATF3 function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:7515060 ATF3 and ATF3 delta Zip. Transcriptional repression versus a...	ACCEPT	Summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length ATF3. Reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that the ATF3 homodimer represses transcription. Supporting Evidence: PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0005634 nucleus	NAS PMID:20102225 Identification of bZIP interaction partners of viral protein...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005634 nucleus	NAS PMID:23661758 Networks of bZIP protein-protein interactions diversified ov...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005634 nucleus	NAS PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005634 nucleus	IDA PMID:7515060 ATF3 and ATF3 delta Zip. Transcriptional repression versus a...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005634 nucleus	NAS PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:20102225 Identification of bZIP interaction partners of viral protein...	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:23661758 Networks of bZIP protein-protein interactions diversified ov...	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:28186491 Combinatorial bZIP dimers display complex DNA-binding specif...	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0006357 regulation of transcription by RNA polymerase II	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor. Reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can repress or activate target transcription depending on dimerization state, isoform, promoter, and cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0045944 positive regulation of transcription by RNA polymerase II	NAS PMID:1406655 Interactions among LRF-1, JunB, c-Jun, and c-Fos define a re...	ACCEPT	Summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts, especially heterodimers and stress-response target promoters. Reason: ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters, ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization. This is real biology, but it should be interpreted together with ATF3 repressor annotations. Supporting Evidence: PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0005634 nucleus	EXP PMID:12034827 An alternatively spliced isoform of transcriptional represso...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0034976 response to endoplasmic reticulum stress	IDA PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas...	KEEP AS NON CORE	Summary: response to endoplasmic reticulum stress is a supported stress-response context for ATF3 but not the core molecular function. Reason: ATF3 is induced downstream of ER stress and ISR/ATF4 signaling and regulates stress-response targets. These process terms are useful context, but the conserved core function remains nuclear transcriptional regulation rather than ER-stress sensing itself. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas...	ACCEPT	Summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts, especially heterodimers and stress-response target promoters. Reason: ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters, ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization. This is real biology, but it should be interpreted together with ATF3 repressor annotations. Supporting Evidence: PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0000122 negative regulation of transcription by RNA polymerase II	TAS PMID:14685163 Roles of CHOP/GADD153 in endoplasmic reticulum stress.	REMOVE	Summary: This CHOP/GADD153 review does not directly support the ATF3 annotation. Reason: The cited reference reviews CHOP/GADD153 roles in ER stress and does not provide direct evidence that ATF3 negatively regulates transcription by RNA polymerase II. ATF3 repression is well supported by other primary ATF3 papers, but this specific TAS-supported row should not be retained on this citation. Supporting Evidence: PMID:14685163 we summarize the current understanding of the roles of CHOP/GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0042803 protein homodimerization activity	IPI PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: ATF3 homodimerization/identical protein binding is an expected bZIP transcription-factor property. Reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is central to DNA recognition and regulatory output. Supporting Evidence: PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription. file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	ISS PMID:18308734 Fibronectin type I repeat is a nonactivating ligand for EphA...	ACCEPT	Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	ISS PMID:18308734 Fibronectin type I repeat is a nonactivating ligand for EphA...	ACCEPT	Summary: ATF3 can act as a context-dependent RNA polymerase II transcriptional activator through heterodimers, splice isoforms, and specific target promoters. Reason: Although canonical full-length ATF3 is often a repressor, published evidence and the deep research synthesis support context-dependent activator activity in specific partner, promoter, and isoform contexts, including Jun/ATF3 promoter activation, ATF3-dependent EphA1 promoter activation, and delta-Zip relief of repression. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS PMID:18308734 Fibronectin type I repeat is a nonactivating ligand for EphA...	ACCEPT	Summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts, especially heterodimers and stress-response target promoters. Reason: ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters, ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization. This is real biology, but it should be interpreted together with ATF3 repressor annotations. Supporting Evidence: PMID:1406655 LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate. PMID:18308734 ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro. PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	MODIFY	Summary: ATF3 sequence-specific RNA polymerase II regulatory DNA binding is well supported, but the more specific cis-regulatory-region child term is preferable. Reason: ATF3 contains a basic region/leucine zipper domain and binds ATF/CRE-like cis-regulatory DNA. GO:0000977 is a valid parent, but GO:0000978 captures the same supported activity more specifically and is already represented in the review. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: ATF3 has direct DNA-binding transcription repressor activity. Reason: Full-length ATF3 represses ATF-site promoters and ATF3 homodimers repress transcription, making this a core molecular function of the canonical full-length protein. Supporting Evidence: PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:1990837 sequence-specific double-stranded DNA binding	IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ...	ACCEPT	Summary: sequence-specific double-stranded DNA binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:16300731 ATF5 increases cisplatin-induced apoptosis through up-regula...	REMOVE	Summary: This citation is for an ATF5 study, not an ATF3 study. Reason: The original publication title and abstract concern ATF5-mediated Cyclin D3 transcription and cisplatin-induced apoptosis. It does not provide direct evidence for ATF3 enabling transcription activator activity or positively regulating RNA polymerase II transcription. Supporting Evidence: PMID:16300731 ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation
GO:0000785 chromatin	ISA GO_REF:0000113	ACCEPT	Summary: Chromatin localization is consistent with ATF3 promoter/enhancer binding as a transcription factor. Reason: ATF3 binding is analyzed by promoter binding, ChIP, and bZIP DNA-binding studies; chromatin is therefore an appropriate active cellular context. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	ISA GO_REF:0000113	ACCEPT	Summary: ATF3 is a DNA-binding RNA polymerase II transcription factor. Reason: The bZIP domain, CRE/ATF-site binding, and extensive transcriptional regulation evidence support this as a core molecular function. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
GO:0000976 transcription cis-regulatory region binding	IDA PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas...	ACCEPT	Summary: transcription cis-regulatory region binding is well supported for ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA. Reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core molecular function, but the PMID:24939851 source row appears to support cis-regulatory involvement mainly by reporter/knockdown evidence rather than a direct binding assay, so its IDA evidence code should be checked at source. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:24939851 A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0003700 DNA-binding transcription factor activity	IGI PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas...	MODIFY	Summary: DNA-binding transcription factor activity is directionally consistent with ATF3 biology but is less specific than existing ATF3 transcription-factor annotations. Reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory DNA binding. The current broad term is true but less informative than the more specific ATF3 terms already supported by IBA, UniProt, and primary literature. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:1903984 positive regulation of TRAIL-activated apoptotic signaling pathway	IMP PMID:24939851 Role of activating transcription factor 3 (ATF3) in endoplas...	KEEP AS NON CORE	Summary: ATF3 promotes TRAIL-mediated apoptosis in a specific ER-stress/cancer-cell context through DR5 induction. Reason: This experimentally supported pathway effect is real, but it is a downstream context-specific consequence of ATF3 transcriptional regulation rather than the conserved core function of the gene product. Supporting Evidence: PMID:24939851 we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
GO:1990622 CHOP-ATF3 complex	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: The CHOP-ATF3 complex annotation is supported by direct ATF3-CHOP/GADD153 interaction evidence. Reason: The cited primary study reports a gadd153/Chop10 heterodimer with ATF3. The complex is biologically informative even though that heterodimer is nonfunctional for ATF/CRE DNA binding and repression. Supporting Evidence: PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length ATF3. Reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that the ATF3 homodimer represses transcription. Supporting Evidence: PMID:7515060 ATF3 represses rather than activates transcription from promoters with ATF sites PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0005634 nucleus	IDA PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0046982 protein heterodimerization activity	IPI PMID:8622660 Analysis of ATF3, a transcription factor induced by physiolo...	ACCEPT	Summary: ATF3 heterodimerization is a core property that determines DNA specificity and transcriptional output. Reason: ATF3-containing heterodimers with bZIP partners are repeatedly documented; partner choice changes DNA-binding specificity and can switch regulatory output. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates. PMID:8622660 ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding	IDA PMID:2516827 Transcription factor ATF cDNA clones: an extensive family of...	MODIFY	Summary: ATF3 sequence-specific RNA polymerase II regulatory DNA binding is well supported, but the more specific cis-regulatory-region child term is preferable. Reason: ATF3 contains a basic region/leucine zipper domain and binds ATF/CRE-like cis-regulatory DNA. GO:0000977 is a valid parent, but GO:0000978 captures the same supported activity more specifically and is already represented in the review. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:2516827 some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA PMID:28186491 Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:16300731 ATF5 increases cisplatin-induced apoptosis through up-regula...	REMOVE	Summary: This citation is for an ATF5 study, not an ATF3 study. Reason: The original publication title and abstract concern ATF5-mediated Cyclin D3 transcription and cisplatin-induced apoptosis. It does not provide direct evidence for ATF3 enabling transcription activator activity or positively regulating RNA polymerase II transcription. Supporting Evidence: PMID:16300731 ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9653893	ACCEPT	Summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9909594	ACCEPT	Summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor. Reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for the active gene product. Supporting Evidence: file:human/ATF3/ATF3-deep-research-falcon.md Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate. PMID:12034827 ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.

Core Functions

ATF3 acts as a nuclear ATF/CREB-family bZIP transcription factor. The full-length protein binds CRE/ATF-like cis-regulatory DNA through its basic region/leucine zipper domain and regulates RNA polymerase II transcription. As a homodimer it commonly represses ATF-site promoters, while heterodimerization with other bZIP factors and delta-Zip isoforms can shift promoter specificity and regulatory output toward activation or relief of repression.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

regulation of transcription by RNA polymerase II

Cellular Locations:

nucleus chromatin

Supporting Evidence:

PMID:7515060
ATF3 represses rather than activates transcription from promoters with ATF sites
PMID:8622660
ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
PMID:2516827
some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
PMID:28186491
Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
file:human/ATF3/ATF3-deep-research-falcon.md
Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.

ATF3 dimerization is an integral part of its transcription-factor mechanism. ATF3 homodimers bind ATF/CRE sites and repress transcription, while ATF3 heterodimers with Jun, ATF/CREB, CHOP/DDIT3, C/EBP, BATF, and related bZIP partners alter DNA-binding specificity and transcriptional output. Generic protein-binding annotations from broad interaction screens should not be treated as core, but the specific bZIP homo- and heterodimerization functions are core to ATF3 biology.

Molecular Function:

protein heterodimerization activity

Directly Involved In:

regulation of transcription by RNA polymerase II

Cellular Locations:

nucleus

Supporting Evidence:

PMID:8622660
ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
PMID:28186491
Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
file:human/ATF3/ATF3-deep-research-falcon.md
Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000113

Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10327051

The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of the c-jun promoter by p300 and 12S E1A.

The cached abstract for this publication focuses on ATF2, p300/CBP, E1A, and the c-jun promoter and does not mention ATF3; the full text was not available locally to verify the IntAct ATF3-JUN interaction record.

"The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of the c-jun promoter by p300 and 12S E1A."

PMID:12034827

An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli.

Stress-induced ATF3DeltaZip2 localizes to nuclei, lacks ATF/CRE binding, and counteracts full-length ATF3 repression.

"ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3."

PMID:1406655

Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase of liver regeneration.

LRF-1/ATF3 with Jun proteins can activate CRE-containing promoters, while LRF-1/JunB can repress c-Fos/c-Jun-mediated activation.

"LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate."

PMID:14685163

Roles of CHOP/GADD153 in endoplasmic reticulum stress.

This CHOP/GADD153 ER-stress review does not directly support an ATF3 annotation.

"we summarize the current understanding of the roles of CHOP/GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease"

PMID:16300731

ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells.

This publication is about ATF5, not ATF3; ATF3 annotations citing it should be removed.

"ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation"

PMID:18255255

A protein-protein interaction network of transcription factors acting during liver cell proliferation.

PMID:18308734

Fibronectin type I repeat is a nonactivating ligand for EphA1 and inhibits ATF3-dependent angiogenesis.

ATF3 can activate transcription of the EphA1 promoter in an ATF3-dependent angiogenesis model.

"ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro."

PMID:19164757

ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells.

PMID:20102225

Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using coiled-coil arrays.

PMID:20211142

An atlas of combinatorial transcriptional regulation in mouse and man.

PMID:23661758

Networks of bZIP protein-protein interactions diversified over a billion years of evolution.

PMID:24939851

Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.

ATF3 mediates ER stress-induced DR5 expression and sensitization to TRAIL-mediated apoptosis in p53-deficient colorectal cancer cells.

"we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells"

PMID:2516827

Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers.

ATF-family bZIP proteins bind ATF sites and form selective DNA-binding heterodimers.

"some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA"

PMID:25609649

Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

PMID:27107012

Pooled-matrix protein interaction screens using Barcode Fusion Genetics.

PMID:28186491

Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.

ATF3 DNA-binding specificity is strongly partner-dependent and best explained by multiple ATF3-containing bZIP dimers.

"Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates."

PMID:28473536

Impact of cytosine methylation on DNA binding specificities of human transcription factors.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29997244

LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.

PMID:30833792

A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.

PMID:31467278

Maximizing binary interactome mapping with a minimal number of assays.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:32911434

A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:37398436

AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.

PMID:38884001

Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.

PMID:7515060

ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms.

Full-length ATF3 represses ATF-site promoters, while ATF3 delta Zip lacks DNA binding and can stimulate transcription by relieving repression.

"ATF3 represses rather than activates transcription from promoters with ATF sites"

PMID:8622660

Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10.

ATF3 is stress induced, binds ATF/CRE DNA as a homodimer, represses transcription, and forms a nonfunctional heterodimer with CHOP/GADD153.

"ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription."

Reactome:R-HSA-9653893

ATF4, CEBPB, and ATF3 bind the CHAC1 promoter

Reactome:R-HSA-9909594

ATF3 binding to CD274 gene

file:human/ATF3/ATF3-deep-research-falcon.md

Falcon deep research report for human ATF3

ATF3 is a stress-inducible nuclear bZIP transcription factor whose core role is partner-dependent transcriptional regulation.

"Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate."
Recent work places ATF3 downstream of ISR/eIF2alpha-ATF4 signaling in several stress-response contexts.

"Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate."

Suggested Experiments

Experiment: Express individual ATF3 isoforms in matched cells and assay ATF/CRE and target-promoter reporters, paired with DNA-binding-defective and leucine-zipper-defective controls.

Hypothesis: Full-length ATF3 and delta-Zip ATF3 isoforms have distinct GO-relevant transcriptional activities.

Type: Isoform-specific reporter assay

Experiment: Profile ATF3 occupancy after perturbing JUN, JUNB, ATF4, DDIT3/CHOP, and selected C/EBP partners, then compare motifs and target gene regulation.

Hypothesis: ATF3 genomic binding specificity depends on its bZIP dimerization partner.

Type: CUT&RUN or ChIP-seq with partner perturbation

Experiment: Validate candidate ATF3 interactors with reciprocal co-immunoprecipitation, DNA-bound complex assays, and reporter readouts to separate specific bZIP dimerization from nonspecific protein-binding evidence.

Hypothesis: Only a subset of high-throughput ATF3 interaction partners represent biologically meaningful transcription-factor dimers.

Type: Focused interaction validation

📚 Additional Documentation

Deep Research Falcon

(ATF3-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
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gene_id: ATF3
gene_symbol: ATF3
uniprot_accession: P18847
protein_description: 'RecName: Full=Cyclic AMP-dependent transcription factor ATF-3
{ECO:0000305}; Short=cAMP-dependent transcription factor ATF-3 {ECO:0000303|PubMed:7515060};
AltName: Full=Activating transcription factor 3;'
gene_info: Name=ATF3 {ECO:0000303|PubMed:7515060, ECO:0000312|HGNC:HGNC:785};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the bZIP family. ATF subfamily. .
protein_domains: AP-1. (IPR000837); bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P18847
Protein Description: RecName: Full=Cyclic AMP-dependent transcription factor ATF-3 {ECO:0000305}; Short=cAMP-dependent transcription factor ATF-3 {ECO:0000303|PubMed:7515060}; AltName: Full=Activating transcription factor 3;
Gene Information: Name=ATF3 {ECO:0000303|PubMed:7515060, ECO:0000312|HGNC:HGNC:785};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the bZIP family. ATF subfamily. .
Key Domains: AP-1. (IPR000837); bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ATF3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'ATF3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene ATF3 (gene ID: ATF3, UniProt: P18847) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P18847
Protein Description: RecName: Full=Cyclic AMP-dependent transcription factor ATF-3 {ECO:0000305}; Short=cAMP-dependent transcription factor ATF-3 {ECO:0000303|PubMed:7515060}; AltName: Full=Activating transcription factor 3;
Gene Information: Name=ATF3 {ECO:0000303|PubMed:7515060, ECO:0000312|HGNC:HGNC:785};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the bZIP family. ATF subfamily. .
Key Domains: AP-1. (IPR000837); bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_1 (PF00170)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ATF3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene ATF3 (gene ID: ATF3, UniProt: P18847) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human ATF3 (UniProt P18847) — Functional Annotation

Scope, identity verification, and nomenclature

This report concerns human ATF3 (Activating Transcription Factor 3), consistent with UniProt accession P18847, a stress-inducible bZIP transcription factor in the ATF/CREB family that binds CRE-like elements and regulates transcription via homo/heterodimerization, including with Jun-family partners (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 2-3, holland2023microglialactivatingtranscription pages 1-3). The reviewed and primary literature summarized below consistently describes ATF3 as a nuclear transcriptional regulator activated by diverse stressors and acting as a context-dependent modulator of inflammatory, cell-death, metabolic, and antiviral programs (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 6-9, badu2024activationofatf3 pages 7-9).

1) Key concepts and definitions (current understanding)

1.1 Molecular function

ATF3 is a basic leucine zipper (bZIP) DNA-binding transcription factor that regulates gene expression by binding promoter/enhancer regulatory sequences, acting as either an activator or repressor depending on dimerization state and cofactors (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 2-3). Recent reviews explicitly report that ATF3 binds the canonical CRE-like motif 5′-TGACGTCA-3′ and can act as a transcriptional repressor or activator through homo- and heterodimers (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 2-3). ATF3 heterodimerization partners named in recent sources include c-JUN, ATF2, and JUNB (liu2024thedualroles pages 2-3, liu2024thedualroles pages 5-6).

1.2 Subcellular localization

ATF3 is described as a nuclear protein (li2023activatingtranscriptionfactor pages 1-3). In a 2024 human-cell infection model (A549), ATF3 protein was reported to show nuclear localization in association with integrated stress response signaling (badu2024activationofatf3 pages 7-9), consistent with its function as a chromatin-associated transcription factor.

1.3 Induction and regulatory logic

ATF3 is widely framed as a rapid stress-response transcriptional effector induced by hypoxia, cytokines, DNA damage, ischemia/reperfusion, oxidative stress, ER stress, and pathogen-associated signaling (li2023activatingtranscriptionfactor pages 1-3, li2023themultifacetedroles pages 1-2, liu2024thedualroles pages 2-3). A key current theme is that ATF3 frequently functions as a feedback modulator of innate immune/inflammatory signaling (not uniformly suppressive—context matters), with effects shaped by partner choice and chromatin/cofactor recruitment (liu2024thedualroles pages 14-15, holland2023microglialactivatingtranscription pages 1-3).

2) Recent developments and latest research (2023–2024 prioritized)

2.1 Integrated stress response (ISR) → ATF4 → ATF3 axis in infection (2024)

A 2024 Journal of Virology study in A549 cells reports that Zika virus infection engages the integrated stress response (ISR) (via eIF2α kinase activation and eIF2α phosphorylation), enabling selective translation of ATF4, which in turn induces ATF3 (badu2024activationofatf3 pages 1-2, badu2024activationofatf3 pages 13-15). Mechanistically, depletion of ATF4 reduced ATF3 RNA/protein, supporting ATF4 as an upstream activator of ATF3 in this setting (badu2024activationofatf3 pages 7-9). Functionally, ATF3 knockout increased viral gene expression, consistent with ATF3 contributing to an antiviral transcriptional program including innate immune genes such as STAT1/ISGs (badu2024activationofatf3 pages 1-2, badu2024activationofatf3 pages 13-15).

2.2 ISR-linked ATF3 promoter binding in degenerative disc inflammation (2024)

A 2024 Experimental & Molecular Medicine paper on intervertebral disc degeneration reports that ISR activation (including increased eIF2α phosphorylation and ATF4 upregulation) leads to ATF3 activation, and ChIP-qPCR verifies ATF3 DNA binding to the promoters of CCL2 and CCL7 in nucleus pulposus cells (tian2024nucleuspulposuscells pages 1-2). This ISR–ATF3–CCL2/7–CCR2 axis is positioned as a mechanistic driver of macrophage recruitment and inflammatory progression in disc degeneration (tian2024nucleuspulposuscells pages 1-2).

2.3 ATF3-driven epigenetic/NF-κB rewiring in acquired drug resistance (2024)

A 2024 Cellular Oncology study of acquired olaparib resistance in pancreatic ductal adenocarcinoma (PDAC) integrates chromatin accessibility and transcriptional profiling to nominate ATF3 as a key transcription factor in resistant cells and links ATF3 to NF-κB pathway activation (liu2024atf3inducedactivationof pages 1-5, liu2024atf3inducedactivationof pages 13-18). The study provides direct mechanistic evidence that ATF3 binds promoters of NF-κB regulators including TRAF1, BIRC3, and ICAM1 (ChIP-seq/ChIP-qPCR) and that ATF3 silencing reduces p-p65 (active NF-κB) and restores olaparib sensitivity (liu2024atf3inducedactivationof pages 18-21, liu2024atf3inducedactivationof pages 8-10).

2.4 Macrophage ATF3 as a metabolic control node in MASH (2024)

A 2024 Science Advances study reports that macrophage Atf3 regulates glucose–fatty acid cycling and modulates hepatocyte steatosis and stellate cell fibrogenesis, positioning ATF3 as a regulator of macrophage metabolic programming with systemic disease consequences (hu2024atf3mediatedmetabolicreprogramming pages 1-2). Importantly for translational relevance, ATF3 protein in CD68+ liver macrophages is reported to be repressed in patients with MASH and shows a strong negative correlation with MASH score (hu2024atf3mediatedmetabolicreprogramming pages 1-2).

3) Current applications and real-world implementations

3.1 Biomarker/therapeutic response indicator in oncology

The PDAC olaparib-resistance study proposes ATF3 as an olaparib sensitivity and prognostic indicator, supported by mechanistic linkage to NF-κB transcriptional control and in vitro/in vivo resensitization strategies via ATF3/NF-κB perturbation (liu2024atf3inducedactivationof pages 13-18, liu2024atf3inducedactivationof pages 18-21). While these are preclinical and not yet standard-of-care clinical implementations, the work provides a concrete example of ATF3 being evaluated as a therapeutic response biomarker and a node for combination therapy design (liu2024atf3inducedactivationof pages 18-21, liu2024atf3inducedactivationof pages 8-10).

3.2 Neuroprotection concepts in ischemic stroke (preclinical)

A 2023 International Journal of Molecular Sciences paper shows that ATF3 overexpression (adenoviral delivery) can reduce infarct burden and neurological deficits in a mouse MCAO model by downregulating CTMP and increasing Akt activation (p-Akt Ser473), while ATF3 knockout worsens outcomes (kao2023activatingtranscriptionfactor pages 1-2, kao2023activatingtranscriptionfactor pages 7-9). The authors also show that post-ischemic CTMP siRNA reduces infarct volume and improves behavior, supporting an ATF3→CTMP→Akt cascade as a modifiable pathway (kao2023activatingtranscriptionfactor pages 7-9).

3.3 Inflammation modulation in CNS and lung disease (expert perspectives)

A 2023 mini-review focusing on acute brain injury emphasizes ATF3 as a master regulator of inflammation with roles in neuroinflammatory responses and proposes biomarker potential for prognosis in acute brain injury contexts (li2023themultifacetedroles pages 1-2). A 2023 pulmonary-disease review frames ATF3 as a potential therapeutic target in inflammatory pulmonary diseases and highlights its stress-inducible nature and regulatory roles in inflammation/innate immunity/ER stress pathways (li2023activatingtranscriptionfactor pages 1-3). A 2023 perspective on microglia argues that ATF3 induction could be leveraged to dampen inflammatory microglial phenotypes and may synergize with neuronal ATF3 programs in disorders involving both neuronal injury and inflammation (holland2023microglialactivatingtranscription pages 1-3).

4) Expert opinions and analysis (authoritative synthesis)

4.1 Why ATF3 appears “dual role” across contexts

Recent expert synthesis emphasizes that ATF3 can function as either transcriptional activator or repressor depending on dimerization composition, chromatin context, and cofactor recruitment (e.g., HDAC1 recruitment to ATF3-bound promoters; coactivator interactions), leading to pro- or anti-inflammatory and pro- or anti-death outputs in different biological contexts (liu2024thedualroles pages 2-3, liu2024thedualroles pages 14-15). Reviews specifically highlight that ATF3’s DNA-binding specificity and downstream outcomes depend on its bZIP dimerization partner, supporting a mechanistic basis for context-dependent outcomes (holland2023microglialactivatingtranscription pages 1-3).

4.2 ATF3 as a stress-to-immunity “wiring” factor

The 2024 ZIKV study is illustrative of ATF3 functioning downstream of ISR signaling to shape innate immunity and antiviral restriction, explicitly linking organelle/cellular stress responses to immune-gene transcription (badu2024activationofatf3 pages 13-15, badu2024activationofatf3 pages 1-2). Similarly, the disc-degeneration study places ATF3 downstream of ISR signaling, but here ATF3 binds chemokine promoters (CCL2/CCL7) and drives macrophage recruitment, illustrating that ATF3 can link stress to either protective or pathogenic inflammation depending on tissue context and downstream targets (tian2024nucleuspulposuscells pages 1-2).

5) Relevant statistics and data from recent studies

5.1 Quantitative oncology data (2024)

In the PDAC acquired-resistance model, olaparib sensitivity shifted markedly: IC50 = 3.355 μM in parental Capan-1 cells versus 69.77 μM in resistant Capan-1-OR cells (liu2024atf3inducedactivationof pages 5-8). Transcriptomics reported 6,043 differentially expressed genes (P < 0.05, |fold change| > 1.5) in resistant cells, and ATAC-seq identified 142 more-accessible and 1,420 less-accessible regions, with ATF3 motif enrichment in resistant cells (liu2024atf3inducedactivationof pages 8-10, liu2024atf3inducedactivationof pages 5-8). Functionally, NF-κB inhibitor parthenolide produced 37.00% apoptosis alone and 63.64% apoptosis when combined with olaparib in this model (liu2024atf3inducedactivationof pages 8-10).

5.2 Quantitative neuroprotection data (2023)

In the ischemic stroke model, CTMP siRNA produced a dose-dependent reduction in infarct volume with significant effects (n ≥ 6; p < 0.05 or p < 0.01) and reduced CTMP protein notably at 75 pmol, increasing p-Akt(473) (but not p-Akt(308)) and decreasing cleaved caspase-3; efficacy persisted when CTMP siRNA was delivered up to 2 h after reperfusion (kao2023activatingtranscriptionfactor pages 7-9).

5.3 Quantitative virology study design details (2024)

In the ZIKV ISR–ATF4–ATF3 work, RT-qPCR analyses used three technical replicates and three biological replicates, repeated across independent experiments, with Student’s t-test and reported significance thresholds (P < 0.05, P < 0.001/0.0005, P < 0.0001) (badu2024activationofatf3 pages 7-9, badu2024activationofatf3 pages 13-15). These details support robustness of the pathway inference even when specific fold-changes are not shown in the extracted text.

Mechanistic summary figure

The following figure schematizes ATF3 induction by stressors and its role in attenuating innate inflammatory signaling (microglia/macrophage paradigm), consistent with the review-level consensus that ATF3 serves as a stress-responsive transcriptional modulator of inflammatory gene expression (holland2023microglialactivatingtranscription media 111e096f).

Evidence-backed functional annotation summary table

Category	Key points	Best recent sources	URL + publication date
Definition/domain	Human ATF3 (UniProt P18847) is consistently described as a stress-inducible nuclear transcription factor in the ATF/CREB family with a basic leucine zipper (bZIP) DNA-binding/dimerization domain, matching the UniProt annotation for human ATF3. Basal expression is low in quiescent cells and rises rapidly after cellular stress. (li2023activatingtranscriptionfactor pages 1-3, li2023themultifacetedroles pages 1-2, liu2024thedualroles pages 2-3)	Li 2023 Immunity, Inflammation and Disease; Li 2023 J Cereb Blood Flow Metab; Liu 2024 Int J Mol Sci	https://doi.org/10.1002/iid3.1028 (Sep 2023); https://doi.org/10.1177/0271678X231171999 (May 2023); https://doi.org/10.3390/ijms25020824 (Jan 2024)
Induction/upstream	ATF3 is induced by diverse stresses including hypoxia, cytokines, DNA damage, ischemia/reperfusion, oxidative stress, ER stress, and pathogen-triggered signaling. Recent primary studies place ATF3 downstream of the integrated stress response (ISR): ZIKV activates PERK/PKR-eIF2α-ATF4 to induce ATF3, and disc degeneration activates eIF2α-ATF4 with ATF3 as a downstream effector. (li2023activatingtranscriptionfactor pages 1-3, badu2024activationofatf3 pages 7-9, tian2024nucleuspulposuscells pages 1-2, inaba2023thetranscriptionfactor pages 10-11)	Li 2023 Immunity, Inflammation and Disease; Badu 2024 J Virol; Tian 2024 Exp Mol Med; Inaba 2023 Nat Commun	https://doi.org/10.1002/iid3.1028 (Sep 2023); https://doi.org/10.1128/jvi.01055-24 (Oct 2024); https://doi.org/10.1038/s12276-024-01168-4 (Feb 2024); https://doi.org/10.1038/s41467-023-35804-w (Jan 2023)
Localization	Review evidence explicitly calls ATF3 a nuclear protein, and in ZIKV-infected A549 cells ATF3 protein shows nuclear localization during ISR-linked activation. Its principal annotated site of action is therefore the nucleus/chromatin compartment, where it regulates transcription. (li2023activatingtranscriptionfactor pages 1-3, badu2024activationofatf3 pages 7-9)	Li 2023 Immunity, Inflammation and Disease; Badu 2024 J Virol	https://doi.org/10.1002/iid3.1028 (Sep 2023); https://doi.org/10.1128/jvi.01055-24 (Oct 2024)
DNA-binding/dimerization	ATF3 binds CRE-like DNA motifs, with the canonical sequence reported as 5′-TGACGTCA-3′. It regulates transcription as a homodimer or heterodimer; named partners include c-JUN, ATF2, and JUNB, and DNA-binding specificity is influenced by the chosen bZIP partner. (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 2-3, holland2023microglialactivatingtranscription pages 1-3, liu2024thedualroles pages 5-6)	Li 2023 Immunity, Inflammation and Disease; Liu 2024 Int J Mol Sci; Holland 2023 Front Mol Neurosci	https://doi.org/10.1002/iid3.1028 (Sep 2023); https://doi.org/10.3390/ijms25020824 (Jan 2024); https://doi.org/10.3389/fnmol.2023.1150296 (Mar 2023)
Direct transcriptional targets	Recent evidence supports direct promoter binding or target regulation for multiple loci: CCL2 and CCL7 in nucleus pulposus cells (ChIP-qPCR), CTMP in ischemic brain, RIPK3 in steatotic liver, and TRAF1, BIRC3, and ICAM1 in olaparib-resistant PDAC (ChIP-seq or ChIP-qPCR). Review synthesis also highlights context-specific targets such as SLC7A11, GPX4, HSP27, BCL2, DR5, and caspase-related genes. (tian2024nucleuspulposuscells pages 1-2, inaba2023thetranscriptionfactor pages 1-2, liu2024atf3inducedactivationof pages 18-21, kao2023activatingtranscriptionfactor pages 7-9, liu2024thedualroles pages 6-9)	Tian 2024 Exp Mol Med; Inaba 2023 Nat Commun; Liu 2024 Cellular Oncology; Kao 2023 Int J Mol Sci; Liu 2024 Int J Mol Sci	https://doi.org/10.1038/s12276-024-01168-4 (Feb 2024); https://doi.org/10.1038/s41467-023-35804-w (Jan 2023); https://doi.org/10.1007/s13402-023-00907-5 (2024); https://doi.org/10.3390/ijms24032306 (Jan 2023); https://doi.org/10.3390/ijms25020824 (Jan 2024)
Pathways	ATF3 functions as a context-dependent transcriptional node linking stress sensing to inflammation, innate immunity, survival, and cell-death pathways. Supported pathways include TLR4-mtROS-dsRNA-ISR-ATF4-ATF3-CCL2 or CCL7-CCR2 signaling in disc degeneration, ISR-ATF4-ATF3 antiviral signaling in ZIKV, ATF3-CTMP-Akt neuroprotection after stroke, ATF3-RIPK3-necroptosis in steatotic liver, NF-κB activation in PARP inhibitor resistance, and macrophage metabolic reprogramming affecting FOXO1, CD36, and RBP4 in MASH. (badu2024activationofatf3 pages 7-9, tian2024nucleuspulposuscells pages 1-2, inaba2023thetranscriptionfactor pages 10-11, hu2024atf3mediatedmetabolicreprogramming pages 1-2, liu2024atf3inducedactivationof pages 13-18, kao2023activatingtranscriptionfactor pages 1-2)	Badu 2024 J Virol; Tian 2024 Exp Mol Med; Inaba 2023 Nat Commun; Hu 2024 Sci Adv; Liu 2024 Cellular Oncology; Kao 2023 Int J Mol Sci	https://doi.org/10.1128/jvi.01055-24 (Oct 2024); https://doi.org/10.1038/s12276-024-01168-4 (Feb 2024); https://doi.org/10.1038/s41467-023-35804-w (Jan 2023); https://doi.org/10.1126/sciadv.ado3141 (Jul 2024); https://doi.org/10.1007/s13402-023-00907-5 (2024); https://doi.org/10.3390/ijms24032306 (Jan 2023)
Disease/translational application	ATF3 is being evaluated as a biomarker and therapeutic lever rather than a routine clinical target. Examples include a candidate olaparib-sensitivity or prognostic marker in PDAC, therapeutic neuroprotection by ATF3 overexpression or CTMP knockdown in ischemic stroke, anti-inflammatory target concepts in pulmonary and CNS disease reviews, and macrophage ATF3 or RBP4 targeting in MASH. (liu2024atf3inducedactivationof pages 13-18, liu2024atf3inducedactivationof pages 18-21, kao2023activatingtranscriptionfactor pages 1-2, li2023themultifacetedroles pages 1-2, li2023activatingtranscriptionfactor pages 1-3, hu2024atf3mediatedmetabolicreprogramming pages 1-2)	Liu 2024 Cellular Oncology; Kao 2023 Int J Mol Sci; Li 2023 J Cereb Blood Flow Metab; Li 2023 Immunity, Inflammation and Disease; Hu 2024 Sci Adv	https://doi.org/10.1007/s13402-023-00907-5 (2024); https://doi.org/10.3390/ijms24032306 (Jan 2023); https://doi.org/10.1177/0271678X231171999 (May 2023); https://doi.org/10.1002/iid3.1028 (Sep 2023); https://doi.org/10.1126/sciadv.ado3141 (Jul 2024)
Quantitative/statistical datapoints	Quantitative examples from recent primary studies include: in PDAC, olaparib IC50 increased from 3.355 μM in parental Capan-1 cells to 69.77 μM in resistant Capan-1-OR cells, with 6,043 DEGs and 142 more-accessible versus 1,420 less-accessible chromatin regions in resistant cells; parthenolide caused 37.00% apoptosis alone and 63.64% with olaparib. In ZIKV work, RT-qPCR and IFN-pathway analyses used 3 technical and 3 biological replicates with significance thresholds including P < 0.05, P < 0.001 or 0.0005, and P < 0.0001. In stroke, CTMP siRNA effects were significant with n ≥ 6 and P < 0.05 or P < 0.01; 75 pmol reduced CTMP protein and infarct burden, and dosing up to 2 h after reperfusion remained effective. (badu2024activationofatf3 pages 7-9, badu2024activationofatf3 pages 13-15, liu2024atf3inducedactivationof pages 8-10, liu2024atf3inducedactivationof pages 5-8, kao2023activatingtranscriptionfactor pages 7-9)	Badu 2024 J Virol; Liu 2024 Cellular Oncology; Kao 2023 Int J Mol Sci	https://doi.org/10.1128/jvi.01055-24 (Oct 2024); https://doi.org/10.1007/s13402-023-00907-5 (2024); https://doi.org/10.3390/ijms24032306 (Jan 2023)

Table: This table summarizes evidence-backed functional annotation facts for human ATF3 (UniProt P18847), emphasizing 2023–2024 reviews and primary studies. It is useful as a compact reference linking ATF3’s molecular identity, mechanisms, pathways, and translational relevance.

Conclusion (functional annotation)

Human ATF3 (UniProt P18847) is best annotated as a stress-inducible, nuclear bZIP transcription factor that binds CRE-like motifs (TGACGTCA) and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate (li2023activatingtranscriptionfactor pages 1-3, liu2024thedualroles pages 2-3, holland2023microglialactivatingtranscription pages 1-3). Recent mechanistic work strengthens a unifying view of ATF3 as a stress-to-transcription coupling factor downstream of ISR/eIF2α–ATF4 signaling in multiple contexts (viral infection, degenerative inflammation, steatotic liver injury) (badu2024activationofatf3 pages 13-15, tian2024nucleuspulposuscells pages 1-2, inaba2023thetranscriptionfactor pages 10-11). Functionally important direct targets supported by recent evidence include CCL2/CCL7, CTMP, RIPK3, and NF-κB regulators such as TRAF1/BIRC3/ICAM1, providing concrete promoter-level anchors for annotation and pathway placement (tian2024nucleuspulposuscells pages 1-2, kao2023activatingtranscriptionfactor pages 7-9, inaba2023thetranscriptionfactor pages 1-2, liu2024atf3inducedactivationof pages 18-21).

URLs and publication dates (selected, most recent prioritized)

Liu S. et al. Int J Mol Sci (Jan 2024): https://doi.org/10.3390/ijms25020824 (liu2024thedualroles pages 2-3)
Badu P. et al. J Virol (Oct 2024): https://doi.org/10.1128/jvi.01055-24 (badu2024activationofatf3 pages 1-2)
Tian S. et al. Exp & Mol Med (Feb 2024): https://doi.org/10.1038/s12276-024-01168-4 (tian2024nucleuspulposuscells pages 1-2)
Hu S. et al. Science Advances (Jul 2024): https://doi.org/10.1126/sciadv.ado3141 (hu2024atf3mediatedmetabolicreprogramming pages 1-2)
Liu Y. et al. Cellular Oncology (2024): https://doi.org/10.1007/s13402-023-00907-5 (liu2024atf3inducedactivationof pages 1-5)
Li D. et al. Immunity, Inflammation and Disease (Sep 2023): https://doi.org/10.1002/iid3.1028 (li2023activatingtranscriptionfactor pages 1-3)
Holland S.D. & Ramer M.S. Front Mol Neurosci (Mar 2023): https://doi.org/10.3389/fnmol.2023.1150296 (holland2023microglialactivatingtranscription pages 1-3)
Li Y. et al. J Cereb Blood Flow Metab (May 2023): https://doi.org/10.1177/0271678X231171999 (li2023themultifacetedroles pages 1-2)
Inaba Y. et al. Nat Commun (Jan 2023): https://doi.org/10.1038/s41467-023-35804-w (inaba2023thetranscriptionfactor pages 1-2)
Kao M.-H. et al. Int J Mol Sci (Jan 2023): https://doi.org/10.3390/ijms24032306 (kao2023activatingtranscriptionfactor pages 1-2)

References

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(tian2024nucleuspulposuscells pages 1-2): Shuo Tian, Xuanzuo Chen, Wei Wu, Hui Lin, Xiangcheng Qing, Sheng Liu, BaiChuan Wang, Yan Xiao, Zengwu Shao, and Yizhong Peng. Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated ccl2/7-ccr2 signaling pathway. Experimental & Molecular Medicine, 56:408-421, Feb 2024. URL: https://doi.org/10.1038/s12276-024-01168-4, doi:10.1038/s12276-024-01168-4. This article has 46 citations and is from a peer-reviewed journal.
(liu2024atf3inducedactivationof pages 1-5): Yang Liu, Yi-lin Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, and Baiyong Shen. Atf3-induced activation of nf-κb pathway results in acquired parp inhibitor resistance in pancreatic adenocarcinoma. Cellular oncology, 47:939-950, Dec 2024. URL: https://doi.org/10.1007/s13402-023-00907-5, doi:10.1007/s13402-023-00907-5. This article has 6 citations and is from a peer-reviewed journal.
(liu2024atf3inducedactivationof pages 13-18): Yang Liu, Yi-lin Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, and Baiyong Shen. Atf3-induced activation of nf-κb pathway results in acquired parp inhibitor resistance in pancreatic adenocarcinoma. Cellular oncology, 47:939-950, Dec 2024. URL: https://doi.org/10.1007/s13402-023-00907-5, doi:10.1007/s13402-023-00907-5. This article has 6 citations and is from a peer-reviewed journal.
(liu2024atf3inducedactivationof pages 18-21): Yang Liu, Yi-lin Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, and Baiyong Shen. Atf3-induced activation of nf-κb pathway results in acquired parp inhibitor resistance in pancreatic adenocarcinoma. Cellular oncology, 47:939-950, Dec 2024. URL: https://doi.org/10.1007/s13402-023-00907-5, doi:10.1007/s13402-023-00907-5. This article has 6 citations and is from a peer-reviewed journal.
(liu2024atf3inducedactivationof pages 8-10): Yang Liu, Yi-lin Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, and Baiyong Shen. Atf3-induced activation of nf-κb pathway results in acquired parp inhibitor resistance in pancreatic adenocarcinoma. Cellular oncology, 47:939-950, Dec 2024. URL: https://doi.org/10.1007/s13402-023-00907-5, doi:10.1007/s13402-023-00907-5. This article has 6 citations and is from a peer-reviewed journal.
(hu2024atf3mediatedmetabolicreprogramming pages 1-2): Shuwei Hu, Rui Li, Dongxu Gong, Pei Hu, Jitu Xu, Yingjie Ai, Xiaojie Zhao, Chencheng Hu, Minghuan Xu, Chenxi Liu, Shuyu Chen, Jie Fan, Zhonghua Zhao, Zhigang Zhang, Huijuan Wu, and Yanyong Xu. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction–associated steatohepatitis. Science Advances, Jul 2024. URL: https://doi.org/10.1126/sciadv.ado3141, doi:10.1126/sciadv.ado3141. This article has 40 citations and is from a highest quality peer-reviewed journal.
(kao2023activatingtranscriptionfactor pages 1-2): Mei-Han Kao, Chien-Yu Huang, Wai-Mui Cheung, Yu-Ting Yan, Jin-Jer Chen, Yuan-Soon Ho, Chung Y. Hsu, and Teng-Nan Lin. Activating transcription factor 3 diminishes ischemic cerebral infarct and behavioral deficit by downregulating carboxyl-terminal modulator protein. International Journal of Molecular Sciences, 24:2306, Jan 2023. URL: https://doi.org/10.3390/ijms24032306, doi:10.3390/ijms24032306. This article has 9 citations.
(kao2023activatingtranscriptionfactor pages 7-9): Mei-Han Kao, Chien-Yu Huang, Wai-Mui Cheung, Yu-Ting Yan, Jin-Jer Chen, Yuan-Soon Ho, Chung Y. Hsu, and Teng-Nan Lin. Activating transcription factor 3 diminishes ischemic cerebral infarct and behavioral deficit by downregulating carboxyl-terminal modulator protein. International Journal of Molecular Sciences, 24:2306, Jan 2023. URL: https://doi.org/10.3390/ijms24032306, doi:10.3390/ijms24032306. This article has 9 citations.
(liu2024atf3inducedactivationof pages 5-8): Yang Liu, Yi-lin Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, and Baiyong Shen. Atf3-induced activation of nf-κb pathway results in acquired parp inhibitor resistance in pancreatic adenocarcinoma. Cellular oncology, 47:939-950, Dec 2024. URL: https://doi.org/10.1007/s13402-023-00907-5, doi:10.1007/s13402-023-00907-5. This article has 6 citations and is from a peer-reviewed journal.
(holland2023microglialactivatingtranscription media 111e096f): Seth D. Holland and Matt S. Ramer. Microglial activating transcription factor 3 upregulation: an indirect target to attenuate inflammation in the nervous system. Frontiers in Molecular Neuroscience, Mar 2023. URL: https://doi.org/10.3389/fnmol.2023.1150296, doi:10.3389/fnmol.2023.1150296. This article has 17 citations.
(inaba2023thetranscriptionfactor pages 10-11): Yuka Inaba, Emi Hashiuchi, Hitoshi Watanabe, Kumi Kimura, Yu Oshima, Kohsuke Tsuchiya, Shin Murai, Chiaki Takahashi, Michihiro Matsumoto, Shigetaka Kitajima, Yasuhiko Yamamoto, Masao Honda, Shun-ichiro Asahara, Kim Ravnskjaer, Shin-ichi Horike, Shuichi Kaneko, Masato Kasuga, Hiroyasu Nakano, Kenichi Harada, and Hiroshi Inoue. The transcription factor atf3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-35804-w, doi:10.1038/s41467-023-35804-w. This article has 59 citations and is from a highest quality peer-reviewed journal.
(inaba2023thetranscriptionfactor pages 1-2): Yuka Inaba, Emi Hashiuchi, Hitoshi Watanabe, Kumi Kimura, Yu Oshima, Kohsuke Tsuchiya, Shin Murai, Chiaki Takahashi, Michihiro Matsumoto, Shigetaka Kitajima, Yasuhiko Yamamoto, Masao Honda, Shun-ichiro Asahara, Kim Ravnskjaer, Shin-ichi Horike, Shuichi Kaneko, Masato Kasuga, Hiroyasu Nakano, Kenichi Harada, and Hiroshi Inoue. The transcription factor atf3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nature Communications, Jan 2023. URL: https://doi.org/10.1038/s41467-023-35804-w, doi:10.1038/s41467-023-35804-w. This article has 59 citations and is from a highest quality peer-reviewed journal.

Citations

li2023activatingtranscriptionfactor pages 1-3
tian2024nucleuspulposuscells pages 1-2
kao2023activatingtranscriptionfactor pages 7-9
li2023themultifacetedroles pages 1-2
holland2023microglialactivatingtranscription pages 1-3
liu2024thedualroles pages 2-3
inaba2023thetranscriptionfactor pages 1-2
kao2023activatingtranscriptionfactor pages 1-2
liu2024thedualroles pages 6-9
liu2024thedualroles pages 5-6
liu2024thedualroles pages 14-15
inaba2023thetranscriptionfactor pages 10-11
https://doi.org/10.1002/iid3.1028
https://doi.org/10.1177/0271678X231171999
https://doi.org/10.3390/ijms25020824
https://doi.org/10.1128/jvi.01055-24
https://doi.org/10.1038/s12276-024-01168-4
https://doi.org/10.1038/s41467-023-35804-w
https://doi.org/10.3389/fnmol.2023.1150296
https://doi.org/10.1007/s13402-023-00907-5
https://doi.org/10.3390/ijms24032306
https://doi.org/10.1126/sciadv.ado3141
https://doi.org/10.1002/iid3.1028,
https://doi.org/10.3390/ijms25020824,
https://doi.org/10.3389/fnmol.2023.1150296,
https://doi.org/10.1128/jvi.01055-24,
https://doi.org/10.1177/0271678x231171999,
https://doi.org/10.1038/s12276-024-01168-4,
https://doi.org/10.1007/s13402-023-00907-5,
https://doi.org/10.1126/sciadv.ado3141,
https://doi.org/10.3390/ijms24032306,
https://doi.org/10.1038/s41467-023-35804-w,

Notes

(ATF3-notes.md)

ATF3 review notes

ATF3 is best treated as a stress-inducible nuclear bZIP transcription factor, not as a generic stress pathway component. The falcon deep-research synthesis describes human ATF3 as a nuclear bZIP factor that binds CRE-like motifs and uses partner-dependent dimerization to remodel transcriptional programs [file:human/ATF3/ATF3-deep-research-falcon.md "Human ATF3 (UniProt P18847) is best annotated as a stress-inducible, nuclear bZIP transcription factor"].

The strongest primary evidence supports full-length ATF3 as a transcriptional repressor at ATF-site promoters and as a context-dependent regulator whose output changes with isoform and dimerization state. Chen et al. report that ATF3 represses ATF-site promoters, while ATF3 delta Zip lacks the leucine zipper, does not bind DNA, and can stimulate transcription PMID:7515060. Hashimoto et al. show stress-induced ATF3DeltaZip2 localizes in nuclei, cannot bind the ATF/CRE motif, and counteracts repression by full-length ATF3 PMID:12034827.

The CHOP/GADD153 interaction is real but should be represented specifically. Chen et al. found that CHOP/GADD153 forms a heterodimer with ATF3, but the heterodimer does not bind ATF/CRE DNA and does not repress transcription, unlike the ATF3 homodimer PMID:8622660.

Positive transcriptional regulation is valid only in context. Evidence includes LRF-1/ATF3 with Jun proteins activating a CRE-containing promoter PMID:1406655, ATF3 stimulating EphA1 promoter activity PMID:18308734, and ATF3-dependent DR5 induction during ER-stress/TRAIL sensitization PMID:24939851.

Generic protein binding rows are over-annotated for this review. ATF3 clearly dimerizes with bZIP partners, and partner choice affects DNA specificity PMID:28186491, but broad interaction-screen annotations should not be used as core functional statements when specific homodimerization, heterodimerization, and transcription-factor complex annotations are available.

Two cited rows appear misattributed. PMID:16300731 is an ATF5 paper, not an ATF3 paper PMID:16300731. PMID:14685163 is a CHOP/GADD153 ER-stress review without direct ATF3 evidence PMID:14685163.

📄 View Raw YAML

id: P18847
gene_symbol: ATF3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATF3 is a human stress-inducible ATF/CREB-family bZIP transcription factor. Its basic region
  and leucine zipper support sequence-specific binding to CRE/ATF-like cis-regulatory DNA and homo- or
  heterodimerization with other bZIP factors. Canonical full-length ATF3 acts primarily as a nuclear RNA
  polymerase II transcriptional regulator, often repressing ATF-site promoters as a homodimer, while heterodimers
  and delta-Zip splice isoforms can produce context-dependent transcriptional activation or relief of
  repression. ATF3 is induced by cellular stress programs including ER stress and integrated stress response
  signaling and links those inputs to gene-expression outputs in inflammation, apoptosis, antiviral response,
  and metabolic stress. These pathway effects are important biological contexts, but the conserved core
  function is partner-dependent transcriptional regulation in the nucleus/chromatin.
alternative_products:
- name: 1 (ATF3)
  id: P18847-1
- name: 2 (ATF3-delta-Zip {ECO:0000303|PubMed:7515060})
  id: P18847-2
  sequence_note: VSP_000592
- name: 3 (ATF3-delta-Zip2a/TF3-delta-Zip2b)
  id: P18847-3
  sequence_note: VSP_043150
- name: 4 (ATF3-delta-Zip2c)
  id: P18847-4
  sequence_note: VSP_043182, VSP_043150
- name: '5'
  id: P18847-5
  sequence_note: VSP_046966
functional_isoforms:
- id: ATF3_FULL_LENGTH
  name: Full-length DNA-binding ATF3
  type: SPLICE_CLASS
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - P18847-1
  description: Full-length ATF3 contains the basic region and leucine zipper domain. It binds ATF/CRE-like
    cis-regulatory DNA as a homodimer or heterodimer and most directly supports the gene-level annotations
    to sequence-specific DNA binding, RNA polymerase II transcription factor activity, transcriptional
    repression, and context-dependent transcriptional activation.
  isoform_specific_terms:
  - id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  - id: GO:0001227
    label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  - id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
- id: ATF3_DELTA_ZIP
  name: Delta-Zip ATF3 isoforms
  type: SPLICE_CLASS
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - P18847-2
    - P18847-3
    - P18847-4
  description: Delta-Zip isoforms lack or disrupt the leucine zipper region needed for canonical bZIP
    dimerization and direct ATF/CRE DNA binding. Published studies report that these isoforms localize
    to nuclei and counteract full-length ATF3-mediated repression, likely by titrating inhibitory cofactors
    rather than by acting as classical DNA-binding transcription factors.
  isoform_specific_terms:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs)
    based on the TFClass database
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10327051
  title: The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of
    the c-jun promoter by p300 and 12S E1A.
  findings:
  - statement: The cached abstract for this publication focuses on ATF2, p300/CBP, E1A, and the c-jun
      promoter and does not mention ATF3; the full text was not available locally to verify the IntAct
      ATF3-JUN interaction record.
    supporting_text: The N-terminal transactivation domain of ATF2 is a target for the co-operative activation
      of the c-jun promoter by p300 and 12S E1A.
- id: PMID:12034827
  title: An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress
    stimuli.
  findings:
  - statement: Stress-induced ATF3DeltaZip2 localizes to nuclei, lacks ATF/CRE binding, and counteracts
      full-length ATF3 repression.
    supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- id: PMID:1406655
  title: Interactions among LRF-1, JunB, c-Jun, and c-Fos define a regulatory program in the G1 phase
    of liver regeneration.
  findings:
  - statement: LRF-1/ATF3 with Jun proteins can activate CRE-containing promoters, while LRF-1/JunB can
      repress c-Fos/c-Jun-mediated activation.
    supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
- id: PMID:14685163
  title: Roles of CHOP/GADD153 in endoplasmic reticulum stress.
  findings:
  - statement: This CHOP/GADD153 ER-stress review does not directly support an ATF3 annotation.
    supporting_text: we summarize the current understanding of the roles of CHOP/GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease
- id: PMID:16300731
  title: ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in
    HeLa cells.
  findings:
  - statement: This publication is about ATF5, not ATF3; ATF3 annotations citing it should be removed.
    supporting_text: ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation
- id: PMID:18255255
  title: A protein-protein interaction network of transcription factors acting during liver cell proliferation.
  findings: []
- id: PMID:18308734
  title: Fibronectin type I repeat is a nonactivating ligand for EphA1 and inhibits ATF3-dependent angiogenesis.
  findings:
  - statement: ATF3 can activate transcription of the EphA1 promoter in an ATF3-dependent angiogenesis
      model.
    supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
- id: PMID:19164757
  title: ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein
    NOXA in cancer cells.
  findings: []
- id: PMID:20102225
  title: Identification of bZIP interaction partners of viral proteins HBZ, MEQ, BZLF1, and K-bZIP using
    coiled-coil arrays.
  findings: []
- id: PMID:20211142
  title: An atlas of combinatorial transcriptional regulation in mouse and man.
  findings: []
- id: PMID:23661758
  title: Networks of bZIP protein-protein interactions diversified over a billion years of evolution.
  findings: []
- id: PMID:24939851
  title: Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced
    sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing
    ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and
    celecoxib.
  findings:
  - statement: ATF3 mediates ER stress-induced DR5 expression and sensitization to TRAIL-mediated apoptosis
      in p53-deficient colorectal cancer cells.
    supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
- id: PMID:2516827
  title: 'Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to
    selectively form DNA-binding heterodimers.'
  findings:
  - statement: ATF-family bZIP proteins bind ATF sites and form selective DNA-binding heterodimers.
    supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
- id: PMID:25609649
  title: Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
  findings: []
- id: PMID:27107012
  title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
  findings: []
- id: PMID:28186491
  title: Combinatorial bZIP dimers display complex DNA-binding specificity landscapes.
  findings:
  - statement: ATF3 DNA-binding specificity is strongly partner-dependent and best explained by multiple
      ATF3-containing bZIP dimers.
    supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- id: PMID:28473536
  title: Impact of cytosine methylation on DNA binding specificities of human transcription factors.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:29997244
  title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping
    of protein-protein interactions in mammalian cells.'
  findings: []
- id: PMID:30833792
  title: A protein-interaction network of interferon-stimulated genes extends the innate immune system
    landscape.
  findings: []
- id: PMID:31467278
  title: Maximizing binary interactome mapping with a minimal number of assays.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread
    Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:32911434
  title: A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE
    transactivation.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:37398436
  title: AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
  findings: []
- id: PMID:38884001
  title: Mapping adipocyte interactome networks by HaloTag-enrichment-mass spectrometry.
  findings: []
- id: PMID:7515060
  title: ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced
    isoforms.
  findings:
  - statement: Full-length ATF3 represses ATF-site promoters, while ATF3 delta Zip lacks DNA binding and
      can stimulate transcription by relieving repression.
    supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
- id: PMID:8622660
  title: Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10.
  findings:
  - statement: ATF3 is stress induced, binds ATF/CRE DNA as a homodimer, represses transcription, and
      forms a nonfunctional heterodimer with CHOP/GADD153.
    supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- id: Reactome:R-HSA-9653893
  title: ATF4, CEBPB, and ATF3 bind the CHAC1 promoter
  findings: []
- id: Reactome:R-HSA-9909594
  title: ATF3 binding to CD274 gene
  findings: []
- id: file:human/ATF3/ATF3-deep-research-falcon.md
  title: Falcon deep research report for human ATF3
  findings:
  - statement: ATF3 is a stress-inducible nuclear bZIP transcription factor whose core role is partner-dependent
      transcriptional regulation.
    supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
  - statement: Recent work places ATF3 downstream of ISR/eIF2alpha-ATF4 signaling in several stress-response
      contexts.
    supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for
      ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ATF3 is a DNA-binding RNA polymerase II transcription factor.
    action: ACCEPT
    reason: The bZIP domain, CRE/ATF-site binding, and extensive transcriptional regulation evidence support
      this as a core molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length
      ATF3.
    action: ACCEPT
    reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that
      the ATF3 homodimer represses transcription.
    supported_by:
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for
      ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0001227
    label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ATF3 has direct DNA-binding transcription repressor activity.
    action: ACCEPT
    reason: Full-length ATF3 represses ATF-site promoters and ATF3 homodimers repress transcription, making
      this a core molecular function of the canonical full-length protein.
    supported_by:
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ATF3 can act as a context-dependent RNA polymerase II transcriptional activator through heterodimers,
      splice isoforms, and specific target promoters.
    action: ACCEPT
    reason: Although canonical full-length ATF3 is often a repressor, published evidence and the deep
      research synthesis support context-dependent activator activity in specific partner, promoter, and
      isoform contexts, including Jun/ATF3 promoter activation, ATF3-dependent EphA1 promoter activation,
      and delta-Zip relief of repression.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of cell population proliferation is reported in disease and stress contexts
      but is a broad downstream phenotype.
    action: KEEP_AS_NON_CORE
    reason: The deep research and older isoform literature describe ATF3 roles in proliferation and cancer
      contexts, but this process is an indirect systems-level outcome of transcriptional regulation and
      should not be treated as core.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: positive regulation of gene expression is directionally consistent with ATF3 biology but
      is less specific than existing ATF3 transcription-factor annotations.
    action: MODIFY
    reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory
      DNA binding. The current broad term is true but less informative than the more specific ATF3 terms
      already supported by IBA, UniProt, and primary literature.
    proposed_replacement_terms:
    - id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: endoplasmic reticulum unfolded protein response is a supported stress-response context for
      ATF3 but not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: ATF3 is induced downstream of ER stress and ISR/ATF4 signaling and regulates stress-response
      targets. These process terms are useful context, but the conserved core function remains nuclear
      transcriptional regulation rather than ER-stress sensing itself.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: cellular response to amino acid starvation is a supported stress-response context for ATF3
      but not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: This IEA row is an orthology-transfer context from mouse Atf3, and amino acid starvation is
      one trigger of the integrated stress response. The reviewed human evidence supports ATF3 as a downstream
      ISR/eIF2alpha-ATF4 transcriptional effector, but the conserved core function remains nuclear transcriptional
      regulation rather than amino-acid starvation sensing itself.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: Automatic transfer of experimentally verified manual GO annotation data to orthologs
        using Ensembl Compara; the GOA row is an amino acid-starvation response annotation transferred
        from mouse Atf3.
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Amino acid starvation is interpreted here as an integrated stress response input;
        recent mechanistic work strengthens a unifying view of ATF3 as a stress-to-transcription coupling
        factor downstream of ISR/eIF2alpha-ATF4 signaling in multiple contexts.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts,
      especially heterodimers and stress-response target promoters.
    action: ACCEPT
    reason: 'ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters,
      ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization.
      This is real biology, but it should be interpreted together with ATF3 repressor annotations.'
    supported_by:
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0070373
    label: negative regulation of ERK1 and ERK2 cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of the ERK1/ERK2 cascade is not a well-supported direct ATF3 function
      in the reviewed human evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: This IEA transfer may reflect a downstream pathway effect in a specific ortholog/context.
      The ATF3 review evidence supports transcriptional regulation and stress-response coupling, but not
      direct negative regulation of ERK signaling as a core annotation.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10327051
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function. Same treatment applied to all other GO:0005515 IPI rows in this review.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18255255
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19164757
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20102225
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20211142
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23661758
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25609649
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107012
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997244
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30833792
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31467278
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32911434
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37398436
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38884001
  review:
    summary: This is a generic protein binding row from interaction data; ATF3 dimerization is real, but
      this term does not capture the informative function.
    action: MARK_AS_OVER_ANNOTATED
    reason: ATF3 function depends on bZIP homo- and heterodimerization, and several interaction screens
      identify ATF3 partners. However, protein binding is too generic for curator use here. Specific dimerization
      annotations and transcription-factor complex annotations better represent the biologically meaningful
      interaction function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18255255
  review:
    summary: ATF3 homodimerization is well supported, but protein homodimerization activity is the more
      specific term.
    action: MODIFY
    reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is
      central to DNA recognition and regulatory output. GO:0042802 is valid but less specific than GO:0042803,
      which captures the same supported homodimerization activity more directly.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
    supported_by:
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23661758
  review:
    summary: ATF3 homodimerization is well supported, but protein homodimerization activity is the more
      specific term.
    action: MODIFY
    reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is
      central to DNA recognition and regulatory output. GO:0042802 is valid but less specific than GO:0042803,
      which captures the same supported homodimerization activity more directly.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
    supported_by:
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNA binding is directionally consistent with ATF3 biology but is less specific than existing
      ATF3 transcription-factor annotations.
    action: MODIFY
    reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory
      DNA binding. The current broad term is true but less informative than the more specific ATF3 terms
      already supported by IBA, UniProt, and primary literature.
    proposed_replacement_terms:
    - id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: DNA-binding transcription factor activity is directionally consistent with ATF3 biology but
      is less specific than existing ATF3 transcription-factor annotations.
    action: MODIFY
    reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory
      DNA binding. The current broad term is true but less informative than the more specific ATF3 terms
      already supported by IBA, UniProt, and primary literature.
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: regulation of DNA-templated transcription is directionally consistent with ATF3 biology but
      is less specific than existing ATF3 transcription-factor annotations.
    action: MODIFY
    reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory
      DNA binding. The current broad term is true but less informative than the more specific ATF3 terms
      already supported by IBA, UniProt, and primary literature.
    proposed_replacement_terms:
    - id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:1990837
    label: sequence-specific double-stranded DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: sequence-specific double-stranded DNA binding is well supported for ATF3 as a bZIP transcription
      factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nucleolus localization is reported in immunofluorescence data but is not the primary site
      of ATF3 transcription-factor action.
    action: KEEP_AS_NON_CORE
    reason: The core supported localization is nucleus/nucleoplasm/chromatin. Nucleolus may be a detected
      subnuclear localization, but the reviewed literature does not make it central to ATF3 function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:7515060
  review:
    summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length
      ATF3.
    action: ACCEPT
    reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that
      the ATF3 homodimer represses transcription.
    supported_by:
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:20102225
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:23661758
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:28186491
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:7515060
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:8622660
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:20102225
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:23661758
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:28186491
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: ATF3 regulates RNA polymerase II transcription as a nuclear bZIP transcription factor.
    action: ACCEPT
    reason: This biological process captures ATF3 core activity at a suitable level, because ATF3 can
      repress or activate target transcription depending on dimerization state, isoform, promoter, and
      cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:1406655
  review:
    summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts,
      especially heterodimers and stress-response target promoters.
    action: ACCEPT
    reason: 'ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters,
      ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization.
      This is real biology, but it should be interpreted together with ATF3 repressor annotations.'
    supported_by:
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:12034827
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:24939851
  review:
    summary: response to endoplasmic reticulum stress is a supported stress-response context for ATF3
      but not the core molecular function.
    action: KEEP_AS_NON_CORE
    reason: ATF3 is induced downstream of ER stress and ISR/ATF4 signaling and regulates stress-response
      targets. These process terms are useful context, but the conserved core function remains nuclear
      transcriptional regulation rather than ER-stress sensing itself.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:24939851
  review:
    summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts,
      especially heterodimers and stress-response target promoters.
    action: ACCEPT
    reason: 'ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters,
      ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization.
      This is real biology, but it should be interpreted together with ATF3 repressor annotations.'
    supported_by:
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:14685163
  review:
    summary: This CHOP/GADD153 review does not directly support the ATF3 annotation.
    action: REMOVE
    reason: The cited reference reviews CHOP/GADD153 roles in ER stress and does not provide direct evidence
      that ATF3 negatively regulates transcription by RNA polymerase II. ATF3 repression is well supported
      by other primary ATF3 papers, but this specific TAS-supported row should not be retained on this
      citation.
    supported_by:
    - reference_id: PMID:14685163
      supporting_text: we summarize the current understanding of the roles of CHOP/GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:8622660
  review:
    summary: ATF3 homodimerization/identical protein binding is an expected bZIP transcription-factor
      property.
    action: ACCEPT
    reason: ATF3 forms homodimers that bind ATF/CRE DNA and repress transcription; this dimerization is
      central to DNA recognition and regulatory output.
    supported_by:
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: ISS
  original_reference_id: PMID:18308734
  review:
    summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding is well supported for
      ATF3 as a bZIP transcription factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: ISS
  original_reference_id: PMID:18308734
  review:
    summary: ATF3 can act as a context-dependent RNA polymerase II transcriptional activator through heterodimers,
      splice isoforms, and specific target promoters.
    action: ACCEPT
    reason: Although canonical full-length ATF3 is often a repressor, published evidence and the deep
      research synthesis support context-dependent activator activity in specific partner, promoter, and
      isoform contexts, including Jun/ATF3 promoter activation, ATF3-dependent EphA1 promoter activation,
      and delta-Zip relief of repression.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: PMID:18308734
  review:
    summary: Positive regulation of RNA polymerase II transcription is supported for specific ATF3 contexts,
      especially heterodimers and stress-response target promoters.
    action: ACCEPT
    reason: 'ATF3 is context-dependent: LRF-1/ATF3 with Jun proteins activates CRE-containing promoters,
      ATF3 stimulates the EphA1 promoter, and ATF3 supports DR5 transcription during ER-stress/TRAIL sensitization.
      This is real biology, but it should be interpreted together with ATF3 repressor annotations.'
    supported_by:
    - reference_id: PMID:1406655
      supporting_text: LRF-1 in combination with either Jun protein strongly activates a cyclic AMP response element-containing promoter which c-Fos/Jun does not activate.
    - reference_id: PMID:18308734
      supporting_text: ATF3 stimulated promoter activity of EphA1 by 3.4-fold in ATF3-dependent angiogenesis in vitro.
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: ATF3 sequence-specific RNA polymerase II regulatory DNA binding is well supported, but the
      more specific cis-regulatory-region child term is preferable.
    action: MODIFY
    reason: ATF3 contains a basic region/leucine zipper domain and binds ATF/CRE-like cis-regulatory DNA.
      GO:0000977 is a valid parent, but GO:0000978 captures the same supported activity more specifically
      and is already represented in the review.
    proposed_replacement_terms:
    - id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0001227
    label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: ATF3 has direct DNA-binding transcription repressor activity.
    action: ACCEPT
    reason: Full-length ATF3 represses ATF-site promoters and ATF3 homodimers repress transcription, making
      this a core molecular function of the canonical full-length protein.
    supported_by:
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:1990837
    label: sequence-specific double-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:28473536
  review:
    summary: sequence-specific double-stranded DNA binding is well supported for ATF3 as a bZIP transcription
      factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:16300731
  review:
    summary: This citation is for an ATF5 study, not an ATF3 study.
    action: REMOVE
    reason: The original publication title and abstract concern ATF5-mediated Cyclin D3 transcription
      and cisplatin-induced apoptosis. It does not provide direct evidence for ATF3 enabling transcription
      activator activity or positively regulating RNA polymerase II transcription.
    supported_by:
    - reference_id: PMID:16300731
      supporting_text: ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: Chromatin localization is consistent with ATF3 promoter/enhancer binding as a transcription
      factor.
    action: ACCEPT
    reason: ATF3 binding is analyzed by promoter binding, ChIP, and bZIP DNA-binding studies; chromatin
      is therefore an appropriate active cellular context.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  review:
    summary: ATF3 is a DNA-binding RNA polymerase II transcription factor.
    action: ACCEPT
    reason: The bZIP domain, CRE/ATF-site binding, and extensive transcriptional regulation evidence support
      this as a core molecular function.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IDA
  original_reference_id: PMID:24939851
  review:
    summary: transcription cis-regulatory region binding is well supported for ATF3 as a bZIP transcription
      factor that binds ATF/CRE-like cis-regulatory DNA.
    action: ACCEPT
    reason: ATF3 contains a basic region/leucine zipper domain, binds ATF/CRE-like regulatory DNA, and
      its in vivo binding specificity is shaped by ATF3-containing homo- and heterodimers. This is a core
      molecular function, but the PMID:24939851 source row appears to support cis-regulatory involvement
      mainly by reporter/knockdown evidence rather than a direct binding assay, so its IDA evidence code
      should be checked at source.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:24939851
      supporting_text: A reporter assay demonstrated that at least two ATF/cAMP response element motifs
        as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter
        were required for ZER-induced DR5 gene transcription.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IGI
  original_reference_id: PMID:24939851
  review:
    summary: DNA-binding transcription factor activity is directionally consistent with ATF3 biology but
      is less specific than existing ATF3 transcription-factor annotations.
    action: MODIFY
    reason: ATF3 is a nuclear bZIP RNA polymerase II transcription factor with sequence-specific cis-regulatory
      DNA binding. The current broad term is true but less informative than the more specific ATF3 terms
      already supported by IBA, UniProt, and primary literature.
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:1903984
    label: positive regulation of TRAIL-activated apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:24939851
  review:
    summary: ATF3 promotes TRAIL-mediated apoptosis in a specific ER-stress/cancer-cell context through
      DR5 induction.
    action: KEEP_AS_NON_CORE
    reason: This experimentally supported pathway effect is real, but it is a downstream context-specific
      consequence of ATF3 transcriptional regulation rather than the conserved core function of the gene
      product.
    supported_by:
    - reference_id: PMID:24939851
      supporting_text: we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells
- term:
    id: GO:1990622
    label: CHOP-ATF3 complex
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: The CHOP-ATF3 complex annotation is supported by direct ATF3-CHOP/GADD153 interaction evidence.
    action: ACCEPT
    reason: The cited primary study reports a gadd153/Chop10 heterodimer with ATF3. The complex is biologically
      informative even though that heterodimer is nonfunctional for ATF/CRE DNA binding and repression.
    supported_by:
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: Negative regulation of RNA polymerase II transcription is a core ATF3 function for full-length
      ATF3.
    action: ACCEPT
    reason: Primary ATF3 studies show that full-length ATF3 represses promoters with ATF sites and that
      the ATF3 homodimer represses transcription.
    supported_by:
    - reference_id: PMID:7515060
      supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:8622660
  review:
    summary: nucleus localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:8622660
  review:
    summary: ATF3 heterodimerization is a core property that determines DNA specificity and transcriptional
      output.
    action: ACCEPT
    reason: ATF3-containing heterodimers with bZIP partners are repeatedly documented; partner choice
      changes DNA-binding specificity and can switch regulatory output.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
    - reference_id: PMID:8622660
      supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:2516827
  review:
    summary: ATF3 sequence-specific RNA polymerase II regulatory DNA binding is well supported, but the
      more specific cis-regulatory-region child term is preferable.
    action: MODIFY
    reason: ATF3 contains a basic region/leucine zipper domain and binds ATF/CRE-like cis-regulatory DNA.
      GO:0000977 is a valid parent, but GO:0000978 captures the same supported activity more specifically
      and is already represented in the review.
    proposed_replacement_terms:
    - id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:2516827
      supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
    - reference_id: PMID:28186491
      supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:16300731
  review:
    summary: This citation is for an ATF5 study, not an ATF3 study.
    action: REMOVE
    reason: The original publication title and abstract concern ATF5-mediated Cyclin D3 transcription
      and cisplatin-induced apoptosis. It does not provide direct evidence for ATF3 enabling transcription
      activator activity or positively regulating RNA polymerase II transcription.
    supported_by:
    - reference_id: PMID:16300731
      supporting_text: ATF5 transcription factor plays an essential role in hematopoietic and glioma cell survival and neuronal cell differentiation
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9653893
  review:
    summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9909594
  review:
    summary: nucleoplasm localization is consistent with ATF3 acting as a nuclear transcription factor.
    action: ACCEPT
    reason: ATF3 is reported as a nuclear protein and experimentally studied as a promoter/chromatin-associated
      transcription factor. Nucleus and nucleoplasm are appropriate cellular component annotations for
      the active gene product.
    supported_by:
    - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
      supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
    - reference_id: PMID:12034827
      supporting_text: ATF3DeltaZip2 protein was shown to be localized in the nuclei and counteracted the transcriptional repression by the full-length ATF3.
core_functions:
- description: ATF3 acts as a nuclear ATF/CREB-family bZIP transcription factor. The full-length protein
    binds CRE/ATF-like cis-regulatory DNA through its basic region/leucine zipper domain and regulates
    RNA polymerase II transcription. As a homodimer it commonly represses ATF-site promoters, while heterodimerization
    with other bZIP factors and delta-Zip isoforms can shift promoter specificity and regulatory output
    toward activation or relief of repression.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:7515060
    supporting_text: ATF3 represses rather than activates transcription from promoters with ATF sites
  - reference_id: PMID:8622660
    supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
  - reference_id: PMID:2516827
    supporting_text: some, but not all, combinations of ATF proteins form heterodimers that efficiently bind to DNA
  - reference_id: PMID:28186491
    supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
  - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
    supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
- description: ATF3 dimerization is an integral part of its transcription-factor mechanism. ATF3 homodimers
    bind ATF/CRE sites and repress transcription, while ATF3 heterodimers with Jun, ATF/CREB, CHOP/DDIT3,
    C/EBP, BATF, and related bZIP partners alter DNA-binding specificity and transcriptional output. Generic
    protein-binding annotations from broad interaction screens should not be treated as core, but the
    specific bZIP homo- and heterodimerization functions are core to ATF3 biology.
  molecular_function:
    id: GO:0046982
    label: protein heterodimerization activity
  directly_involved_in:
  - id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:8622660
    supporting_text: ATF3-interacting protein gadd153/Chop10 forms a nonfunctional heterodimer with ATF3; the heterodimer, in contrast to the ATF3 homodimer, does not bind to the ATF/cyclic AMP response element consensus site and does not repress transcription.
  - reference_id: PMID:28186491
    supporting_text: Genome-wide binding of ATF3 is best explained by considering many dimers in which it participates.
  - reference_id: file:human/ATF3/ATF3-deep-research-falcon.md
    supporting_text: Human ATF3 is best annotated as a stress-inducible nuclear bZIP transcription factor that binds CRE-like motifs and acts via partner-dependent dimerization to remodel transcriptional programs across stress, immunity, metabolism, and cell fate.
proposed_new_terms: []
suggested_questions:
- question: Should ATF3 delta-Zip isoforms receive isoform-specific GO annotations that distinguish cofactor-sequestration/relief-of-repression
    activity from canonical full-length DNA-binding transcription factor activity?
  experts:
  - Tsonwin Hai
  - Shigetaka Kitajima
- question: Can the ATF3 protein-binding rows from high-throughput interaction screens be replaced by
    specific bZIP dimerization or transcription-factor complex annotations where the partner and mechanism
    are clear?
  experts: []
- question: Should annotations citing PMID:16300731 and PMID:14685163 be corrected at source because the
    former is an ATF5 paper and the latter is a CHOP/GADD153 ER-stress review without direct ATF3 evidence?
  experts: []
- question: Should the GOA source row for GO:0000976 citing PMID:24939851 be reviewed for evidence-code
    accuracy, since the cached abstract supports ATF3-dependent DR5 reporter transcription but not a direct
    ATF3 binding assay?
  experts: []
- question: Should the GOA rows using ISS with PMID:18308734 be reviewed for evidence-code accuracy,
    since the publication directly studies ATF3-dependent EphA1 promoter activation rather than inferring
    function from sequence or structural similarity?
  experts: []
suggested_experiments:
- experiment_type: Isoform-specific reporter assay
  hypothesis: Full-length ATF3 and delta-Zip ATF3 isoforms have distinct GO-relevant transcriptional activities.
  description: Express individual ATF3 isoforms in matched cells and assay ATF/CRE and target-promoter
    reporters, paired with DNA-binding-defective and leucine-zipper-defective controls.
- experiment_type: CUT&RUN or ChIP-seq with partner perturbation
  hypothesis: ATF3 genomic binding specificity depends on its bZIP dimerization partner.
  description: Profile ATF3 occupancy after perturbing JUN, JUNB, ATF4, DDIT3/CHOP, and selected C/EBP
    partners, then compare motifs and target gene regulation.
- experiment_type: Focused interaction validation
  hypothesis: Only a subset of high-throughput ATF3 interaction partners represent biologically meaningful
    transcription-factor dimers.
  description: Validate candidate ATF3 interactors with reciprocal co-immunoprecipitation, DNA-bound complex
    assays, and reporter readouts to separate specific bZIP dimerization from nonspecific protein-binding
    evidence.

ATF3

Gene Description

Functional Isoforms

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Comprehensive Research Report: Human ATF3 (UniProt P18847) — Functional Annotation

Scope, identity verification, and nomenclature

1) Key concepts and definitions (current understanding)

1.1 Molecular function

1.2 Subcellular localization

1.3 Induction and regulatory logic

2) Recent developments and latest research (2023–2024 prioritized)

2.1 Integrated stress response (ISR) → ATF4 → ATF3 axis in infection (2024)

2.2 ISR-linked ATF3 promoter binding in degenerative disc inflammation (2024)

2.3 ATF3-driven epigenetic/NF-κB rewiring in acquired drug resistance (2024)

2.4 Macrophage ATF3 as a metabolic control node in MASH (2024)

3) Current applications and real-world implementations

3.1 Biomarker/therapeutic response indicator in oncology

3.2 Neuroprotection concepts in ischemic stroke (preclinical)

3.3 Inflammation modulation in CNS and lung disease (expert perspectives)

4) Expert opinions and analysis (authoritative synthesis)

4.1 Why ATF3 appears “dual role” across contexts

4.2 ATF3 as a stress-to-immunity “wiring” factor

5) Relevant statistics and data from recent studies

5.1 Quantitative oncology data (2024)

5.2 Quantitative neuroprotection data (2023)

5.3 Quantitative virology study design details (2024)

Mechanistic summary figure

Evidence-backed functional annotation summary table

Conclusion (functional annotation)

URLs and publication dates (selected, most recent prioritized)

Citations

Notes

ATF3 review notes

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