GADD45A

Existing Annotations Review

Gene Description

Existing Annotations Review

Core Functions

Activates stress-responsive MAPK signaling (p38 and JNK cascades) by binding to and activating MTK1/MEKK4 (MAP3K4). GADD45A binding releases MTK1 autoinhibition by inducing dissociation of the N-terminal and C-terminal domains, enabling kinase dimerization and autophosphorylation.

Induces G2/M cell cycle arrest by directly binding and inhibiting the Cdc2/cyclin B1 complex. GADD45A binds Cdc2 through its central region (aa 65-84) and promotes dissociation of the Cdc2/cyclin B1 complex, suppressing kinase activity required for mitotic entry.

Regulates Aurora A kinase activity through direct binding. GADD45A interacts with Aurora A through its dimerization interface, potentially competing with GADD45A self-association. This interaction may regulate centrosome stability and mitotic progression.

References

Deep Research

Cyberian

Falcon

Perplexity

📄 View Raw YAML

GO Term	Evidence	Action	Reason
GO:0051726 regulation of cell cycle	IBA GO_REF:0000033	ACCEPT	Summary: GADD45A is a well-established cell cycle regulator, primarily mediating G2/M arrest through inhibition of Cdc2/cyclin B1 complex. GADD45A binds directly to Cdc2 via its central region (aa 65-84) and inhibits Cdc2 kinase activity by promoting dissociation of the Cdc2/cyclin B1 complex [PMID:10747892 "GADD45-induced cell cycle G2-M arrest was abolished when its Cdc2 binding motif was disrupted"]. IBA annotation is appropriate as this function is conserved across GADD45 family members. Supporting Evidence: file:human/GADD45A/GADD45A-deep-research-perplexity.md See deep research file for comprehensive analysis file:human/GADD45A/GADD45A-deep-research-falcon.md GADD45A disrupts/antagonizes the CDK1(CDC2)-Cyclin B1 machinery and associated PLK1/CDC25C loop, promoting G2/M arrest after stress PMID:39458909 GADD45A induces cell G2/M cycle arrest and inhibits cell proliferation by interacting with CDK1, thereby inducing the dissociation of the CDK1-Cyclin B1 complex, which inhibits the kinase activity of CDK1
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: GADD45A is primarily a nuclear protein. Multiple IDA evidence confirms nuclear localization [PMID:7973727, PMID:9827804, PMID:20460379]. IBA annotation is supported by experimental evidence and is correct.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: While GADD45A is primarily nuclear, IDA evidence from PMID:9827804 (Takekawa & Saito 1998) shows cytoplasmic localization as well. The protein can shuttle between compartments and interact with cytoplasmic kinases like MTK1/MEKK4.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Nuclear localization is well supported by experimental evidence. This IEA annotation is redundant with IBA and IDA annotations for the same term. However, it is correct.
GO:0006974 DNA damage response	IEA GO_REF:0000043	ACCEPT	Summary: GADD45A is named for its role as a DNA Damage-inducible gene. It is transcriptionally induced by ionizing radiation, UV, and alkylating agents and functions downstream of p53 in the DNA damage response [PMID:7973727 "GADD45 is a ubiquitously expressed mammalian gene that is induced by DNA damage"]. The term is appropriate for this core function. Supporting Evidence: PMID:40083548 Growth arrest and DNA damage-inducible 45 (GADD45) proteins are critical stress sensors rapidly induced in response to genotoxic/physiological stress and regulate many cellular functions file:human/GADD45A/GADD45A-deep-research-falcon.md GADD45A is widely characterized as a stress-sensor protein induced by genotoxic and physiological stresses and acting predominantly through protein–protein interactions (i.e., it is not an enzyme with a defined catalytic reaction)
GO:0046330 positive regulation of JNK cascade	IEA GO_REF:0000117	ACCEPT	Summary: GADD45A activates JNK through direct binding to and activation of MTK1/MEKK4 (MAP3K4). This is a core function well-supported by experimental evidence [PMID:9827804 "GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK... Expression of the GADD45-like genes induces p38/JNK activation"]. IEA annotation is correct. Supporting Evidence: PMID:38568424 The GADD45 enzymes are MAP3K4 activating agents, adhering to its N-terminal part, and preventing the autoinhibitory region from blocking the kinase domain when they are attached to that area file:human/GADD45A/GADD45A-deep-research-falcon.md GADD45 proteins bind the N-terminal region of MAP3K4/MEKK4/MTK1, preventing an autoinhibitory domain from blocking the kinase domain, thereby enabling downstream engagement of p38 and JNK signaling
GO:0051726 regulation of cell cycle	IEA GO_REF:0000120	ACCEPT	Summary: Redundant with IBA annotation (same term). Cell cycle regulation is a core function of GADD45A, primarily through G2/M checkpoint control via Cdc2/cyclin B1 inhibition.
GO:1900745 positive regulation of p38MAPK cascade	IEA GO_REF:0000117	ACCEPT	Summary: GADD45A activates p38 MAPK through MTK1/MEKK4 binding and activation. This is a well-established core function [PMID:9827804 "GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK... induces p38/JNK activation"]. p38 activation contributes to downstream effects including ROS production and senescence [PMID:20160708]. Supporting Evidence: PMID:38568424 The GADD45 enzymes are MAP3K4 activating agents, adhering to its N-terminal part, and preventing the autoinhibitory region from blocking the kinase domain when they are attached to that area file:human/GADD45A/GADD45A-deep-research-falcon.md GADD45 proteins bind the N-terminal region of MAP3K4/MEKK4/MTK1, preventing an autoinhibitory domain from blocking the kinase domain, thereby enabling downstream engagement of p38 and JNK signaling
GO:0016525 negative regulation of angiogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GADD45A suppresses angiogenesis via inhibition of the mTOR/STAT3 pathway, reducing VEGFa expression [PMID:23329839 "Gadd45a plays an important role in suppression of tumor angiogenesis"]. This is a tumor suppressor function but may be considered non-core as it is indirect and context-dependent.
GO:0043537 negative regulation of blood vessel endothelial cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: This annotation is related to GADD45A tumor suppressor function. Supported by PMID:23329839 showing GADD45A deletion promotes endothelial cell migration. This is a downstream effect of mTOR/STAT3 pathway inhibition, not a direct function.
GO:1990841 promoter-specific chromatin binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: GADD45A binds to R-loops at gene promoters and recruits TET1 demethylase for site-specific DNA demethylation. Deep research cites evidence that GADD45A directly binds R-loops in an RNA-dependent manner and is recruited to CpG island promoters. However, this annotation is based on Ensembl ortholog transfer (IEA) and may reflect findings primarily from mouse studies. The molecular function may be more accurately described as R-loop binding.
GO:0005515 protein binding	IPI PMID:12052864 Regulation of MTK1/MEKK4 kinase activity by its N-terminal a...	MARK AS OVER ANNOTATED	Summary: This paper describes GADD45 binding to MTK1/MEKK4 N-terminal autoinhibitory domain. "Protein binding" is too vague - this represents kinase binding activity enabling MAPKKK activation. A more specific term like kinase binding (GO:0019900) would be preferable. Supporting Evidence: PMID:12052864 Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding.
GO:0005515 protein binding	IPI PMID:12716909 CR6-interacting factor 1 interacts with Gadd45 family protei...	MARK AS OVER ANNOTATED	Summary: This paper shows GADD45A interaction with GADD45GIP1 (CR6-interacting factor 1), which modulates the cell cycle. "Protein binding" is too vague for this specific interaction. Supporting Evidence: PMID:12716909 2003 Apr 25. CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome mapping study. "Protein binding" is uninformative. Large-scale protein interaction screens without specific functional characterization do not warrant specific annotations. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17268471 Gadd45a promotes epigenetic gene activation by repair-mediat...	MARK AS OVER ANNOTATED	Summary: This paper describes GADD45A role in epigenetic gene activation through DNA demethylation. The interaction with TDG and involvement in BER-mediated demethylation is more specifically captured by other annotations. Supporting Evidence: PMID:17268471 Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation.
GO:0005515 protein binding	IPI PMID:21722948 Thymine DNA glycosylase is essential for active DNA demethyl...	MARK AS OVER ANNOTATED	Summary: This paper describes TDG-mediated DNA demethylation pathway involving GADD45A. The specific functional interaction is with TDG for base excision repair. "Protein binding" is uninformative. Supporting Evidence: PMID:21722948 Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: High-throughput protein interaction study in human liver. "Protein binding" from large-scale screens is uninformative without specific functional context. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:23329839 Gadd45a suppresses tumor angiogenesis via inhibition of the ...	MARK AS OVER ANNOTATED	Summary: This paper describes GADD45A interaction with mTOR to inhibit STAT3 phosphorylation. "Protein binding" is too vague - a more specific annotation capturing mTOR binding or kinase regulation would be more appropriate. Supporting Evidence: PMID:23329839 2013 Jan 17. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
GO:0005515 protein binding	IPI PMID:23820005 Activation-induced cytidine deaminase auto-activates and tri...	MARK AS OVER ANNOTATED	Summary: This paper describes AICDA (activation-induced cytidine deaminase) interactions. The UniProt entry shows GADD45A-AICDA interaction. "Protein binding" is uninformative. Supporting Evidence: PMID:23820005 Epub 2013 Jun 29. Activation-induced cytidine deaminase auto-activates and triggers aberrant gene expression.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput binary protein interactome map. "Protein binding" from large-scale screens without functional characterization is uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Interactome mapping in neurodegenerative disease context. "Protein binding" is too generic without specific functional characterization. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale interactome network. "Protein binding" from large-scale screens is uninformative without specific functional context. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc...	MARK AS OVER ANNOTATED	Summary: AI-guided protein-protein interaction study for drug discovery. "Protein binding" is too generic without functional characterization. Supporting Evidence: PMID:37398436 AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study. "Protein binding" from large-scale characterization is uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0016607 nuclear speck	IDA GO_REF:0000052	ACCEPT	Summary: GADD45A localizes to nuclear speckles, particularly under stress conditions. PMID:21249130 demonstrates RNase-sensitive localization within nuclear speckles with SC35 and p68 colocalization. RNase treatment reduces nuclear speckle localization from 72% to 20% of cells, indicating RNA binding is essential for this localization. The G39 residue is critical for both RNA binding and nuclear speckle localization. This localization is functionally relevant for DNA demethylation at active transcription sites. Supporting Evidence: PMID:21249130 Gadd45a is an RNA binding protein and is localized in nuclear speckles.
GO:0005515 protein binding	IDA PMID:20460379 Solution structure of human growth arrest and DNA damage 45a...	MARK AS OVER ANNOTATED	Summary: This paper reports the NMR structure of GADD45A and its interactions with PCNA and Aurora A kinase. The specific interactions (kinase binding, homodimerization) are captured by other annotations from the same paper. Generic "protein binding" is uninformative. Supporting Evidence: PMID:20460379 2010 May 11. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase.
GO:0019900 kinase binding	IPI PMID:20460379 Solution structure of human growth arrest and DNA damage 45a...	ACCEPT	Summary: PMID:20460379 demonstrates direct binding of GADD45A to Aurora A kinase (AURKA) through the dimerization interface region. This is a core molecular function. GADD45A also binds MTK1/MEKK4, another kinase. Kinase binding is more specific and informative than generic "protein binding". Supporting Evidence: PMID:20460379 2010 May 11. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase. PMID:38568424 The GADD45 enzymes are MAP3K4 activating agents, adhering to its N-terminal part, and preventing the autoinhibitory region from blocking the kinase domain when they are attached to that area
GO:0042803 protein homodimerization activity	IDA PMID:20460379 Solution structure of human growth arrest and DNA damage 45a...	ACCEPT	Summary: PMID:20460379 demonstrates GADD45A homodimerization through NMR analysis. The protein is predominantly monomeric but exists in equilibrium with dimers and oligomers whose population increases with concentration. The L77E mutation abolishes dimerization [PMID:20460379 "L77E mutation abolishes dimerization"]. Dimerization is a regulatory mechanism affecting interactions with partners like Aurora A. Supporting Evidence: PMID:20460379 2010 May 11. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase.
GO:0046982 protein heterodimerization activity	IPI PMID:20460379 Solution structure of human growth arrest and DNA damage 45a...	ACCEPT	Summary: GADD45A can form heterodimers with other GADD45 family members (GADD45B, GADD45G). This heterodimerization has been detected by co-immunoprecipitation in mammalian cells. The dimerization interface involves helices alpha2 and alpha3. Supporting Evidence: PMID:20460379 2010 May 11. Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:23329839 Gadd45a suppresses tumor angiogenesis via inhibition of the ...	KEEP AS NON CORE	Summary: PMID:23329839 shows GADD45A suppresses STAT3 transcriptional activity by inhibiting STAT3 Ser-727 phosphorylation via mTOR pathway disruption. This leads to reduced VEGFa expression. While the evidence shows GADD45A affects transcription downstream of STAT3, this is an indirect effect on specific genes rather than a direct transcriptional regulatory function. Supporting Evidence: PMID:23329839 2013 Jan 17. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
GO:0071901 negative regulation of protein serine/threonine kinase activity	IMP PMID:23329839 Gadd45a suppresses tumor angiogenesis via inhibition of the ...	KEEP AS NON CORE	Summary: PMID:23329839 shows GADD45A physically associates with mTOR and disrupts the mTOR-STAT3 interaction, suppressing mTOR-mediated STAT3 Ser-727 phosphorylation. This represents kinase regulation through sequestration rather than direct inhibition. This is context-specific tumor suppressor function. Supporting Evidence: PMID:23329839 2013 Jan 17. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
GO:0033140 negative regulation of peptidyl-serine phosphorylation of STAT protein	IMP PMID:23329839 Gadd45a suppresses tumor angiogenesis via inhibition of the ...	KEEP AS NON CORE	Summary: PMID:23329839 demonstrates that GADD45A suppresses STAT3 phosphorylation at Ser-727 specifically [PMID:23329839 "Gadd45a disruption increases P-Ser STAT3... Gadd45a overexpression reduces P-Ser STAT3"]. The mechanism involves disrupting mTOR-STAT3 interaction. This is a specific mechanism of tumor suppressor activity. Supporting Evidence: PMID:23329839 2013 Jan 17. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
GO:0043537 negative regulation of blood vessel endothelial cell migration	IMP PMID:23329839 Gadd45a suppresses tumor angiogenesis via inhibition of the ...	KEEP AS NON CORE	Summary: PMID:23329839 shows GADD45A deletion promotes endothelial cell migration and tube formation [PMID:23329839 "Disruption of endogenous Gadd45a promotes tube formation and migration of endothelial cells"]. This is a downstream effect of the mTOR/STAT3/VEGFa pathway regulation. Redundant with IEA annotation. Supporting Evidence: PMID:23329839 2013 Jan 17. Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.
GO:0005634 nucleus	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: PMID:9827804 (Takekawa & Saito 1998, Cell) confirms nuclear localization of GADD45A. Redundant with other nucleus annotations but supported by experimental evidence. Supporting Evidence: PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.
GO:0005737 cytoplasm	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: PMID:9827804 shows cytoplasmic localization as well as nuclear. GADD45A interacts with cytoplasmic MTK1/MEKK4 to activate p38/JNK cascades, consistent with cytoplasmic presence. Supporting Evidence: PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.
GO:0043065 positive regulation of apoptotic process	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: PMID:9827804 demonstrates GADD45A expression induces apoptosis via p38/JNK activation [PMID:9827804 "Expression of the GADD45-like genes induces p38/JNK activation and apoptosis"]. This apoptosis-promoting function is context-dependent (cell type specific) but is a well-established function when GADD45A is overexpressed. Supporting Evidence: PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. file:human/GADD45A/GADD45A-deep-research-falcon.md GADD45A can promote apoptosis through p38/JNK-linked stress signaling, often in the context of DNA damage or oxidative stress
GO:0046330 positive regulation of JNK cascade	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: PMID:9827804 is the key paper establishing GADD45A activates JNK through MTK1/MEKK4 binding [PMID:9827804 "GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK"]. This is a core function with direct assay evidence. The paper shows GADD45A binds to MTK1 N-terminal domain and activates its kinase activity both in vivo and in vitro. Supporting Evidence: PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. PMID:38568424 MAP3K4 initiation may occur when a molecule like DNA-damage-inducible 45 (GADD45) prevents the N-terminal domain from inhibiting the functional region anymore
GO:1900745 positive regulation of p38MAPK cascade	IDA PMID:9827804 A family of stress-inducible GADD45-like proteins mediate ac...	ACCEPT	Summary: PMID:9827804 demonstrates GADD45A activates p38 MAPK pathway through MTK1/MEKK4 activation [PMID:9827804 "induces p38/JNK activation"]. This is a core function with direct experimental evidence. GADD45A binding releases MTK1 autoinhibition, enabling kinase activation. Supporting Evidence: PMID:9827804 A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. PMID:38568424 MAP3K4 initiation may occur when a molecule like DNA-damage-inducible 45 (GADD45) prevents the N-terminal domain from inhibiting the functional region anymore
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3215144	ACCEPT	Summary: Reactome pathway annotation for p53-mediated GADD45A transcription. Nucleoplasm localization is consistent with GADD45A nuclear function and its role in PCNA and Aurora A binding within the nucleus.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6791109	ACCEPT	Summary: Reactome annotation for GADD45A-PCNA binding. Nucleoplasm is appropriate as GADD45A interacts with PCNA at sites of DNA replication/repair in the nuclear compartment.