RAD18

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: RAD18 is localized to the nucleus where it carries out its DNA damage tolerance functions. Multiple studies confirm nuclear localization: PMID:10884424 identified hRAD18 as nuclear, PMID:15632077 showed RAD18 colocalizes with BRCTx in the nucleus, PMID:22036607 demonstrated nuclear localization and nuclear inclusion body formation, and PMID:25023518 showed nuclear foci formation after DNA damage. Reason: Nuclear localization is well-supported by multiple experimental studies. The IBA annotation is phylogenetically consistent with experimental evidence from human and model organisms. Supporting Evidence: PMID:10884424 hRad18 protein binds to hHR6 protein through a conserved ring-finger motif PMID:15632077 BRCTx binds to the C terminus of hRAD18 in yeast two-hybrid and immunoprecipitation assays and colocalizes with this protein in the nucleus PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage file:human/RAD18/RAD18-deep-research-falcon.md model: Edison Scientific Literature
GO:0006301 DNA damage tolerance	IBA GO_REF:0000033	ACCEPT	Summary: DNA damage tolerance is the core biological process of RAD18. RAD18-mediated PCNA monoubiquitination is the key initiating event for translesion synthesis and template switching, both major branches of DDT. Loss of RAD18 results in defective postreplication repair and hypersensitivity to UV, MMS, and mitomycin C (PMID:10884424). Recent studies (Chen et al. 2024, Ma et al. 2024) confirm RAD18's central role in DDT through PCNA ubiquitination. Reason: This is the primary biological process annotation for RAD18 and is strongly supported by extensive literature. The IBA annotation correctly captures the core function. Supporting Evidence: PMID:10884424 Stable transformants with hRad18 mutated in this motif become sensitive to UV, methyl methanesulfonate, and mitomycin C, and are defective in the replication of UV-damaged DNA PMID:10908344 Through interaction and complex formation with HHR6A and HHR6B, RAD18 protein may play an important role in lesion bypass mechanisms in humans
GO:0006513 protein monoubiquitination	IBA GO_REF:0000033	ACCEPT	Summary: RAD18, together with E2 RAD6, catalyzes monoubiquitination of PCNA at Lys164. This is the primary enzymatic output of RAD18 activity. Multiple studies confirm this including PMID:18363965 which shows the SAP domain is required for efficient mono-ubiquitination of PCNA, and PMID:25023518 which demonstrates that Rad18 is required for PCNA monoubiquitination. Reason: Protein monoubiquitination accurately describes RAD18's enzymatic activity on its primary substrate PCNA. This is a core function annotation. Supporting Evidence: PMID:18363965 The SAP domain is also required for the efficient mono-ubiquitination of PCNA PMID:25023518 Rad18 is a central E3 ubiquitin ligase in DDT, which exists in a monoubiquitinated (Rad18•Ub) and nonubiquitinated form in human cells
GO:0097505 Rad6-Rad18 complex	IBA GO_REF:0000033	ACCEPT	Summary: RAD18 forms a stable complex with RAD6 (UBE2A/UBE2B in humans) that is essential for its E3 ubiquitin ligase function. PMID:10908344 demonstrated that human RAD18 interacts with HHR6A and HHR6B, with stable protein complexes identified and purified. PMID:10884424 showed hRad18 binds to hHR6 through the conserved ring-finger motif. PMID:18363965 confirmed that RAD18 complexed with RAD6B is recruited to stalled replication forks. Reason: Complex formation with RAD6 is essential for RAD18 function and is well-supported by multiple experimental studies in human cells. Supporting Evidence: PMID:10908344 Human RAD18 protein (hRAD18) was found to interact with HHR6A and HHR6B. When co-expressed in yeast cells, stable hRAD18-HHR6A and hRAD18-HHR6B protein complexes were identified and purified to near homogeneity PMID:10884424 In vivo, hRad18 protein binds to hHR6 protein through a conserved ring-finger motif
GO:0003677 DNA binding	IEA GO_REF:0000120	ACCEPT	Summary: RAD18 binds DNA through its SAP domain, with preference for forked and single-stranded DNA structures. PMID:18363965 provides direct experimental evidence that RAD18 complexed with RAD6B preferentially binds to forked and ssDNA structures, with the SAP domain (residues 248-282) being crucial for DNA binding. Reason: DNA binding is experimentally validated. The IEA annotation is correct and supported by direct evidence in PMID:18363965. Supporting Evidence: PMID:18363965 Human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures
GO:0003697 single-stranded DNA binding	IEA GO_REF:0000002	ACCEPT	Summary: PMID:18363965 directly demonstrated that RAD18-RAD6B complex binds to ssDNA structures localized at stalled replication forks. This binding is mediated by the SAP domain. Reason: The IEA annotation is validated by experimental evidence. ssDNA binding is a more specific annotation than general DNA binding and accurately reflects RAD18's substrate preference. Supporting Evidence: PMID:18363965 Human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures, which are known to be localized at stalled replication forks
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate annotation of nucleus localization, also supported by IBA evidence. Well-validated experimentally (see IBA annotation review above). Reason: Correct annotation, duplicative with IBA but acceptable. Supporting Evidence: PMID:15632077 colocalizes with this protein in the nucleus
GO:0005694 chromosome	IEA GO_REF:0000117	ACCEPT	Summary: RAD18 functions at replication forks and DNA damage sites on chromosomes. Its localization to chromatin during DNA damage response is well-documented, including localization to stalled replication forks and sites of double-strand breaks. Reason: RAD18's association with chromosomes during replication stress and DNA damage is consistent with its function. Supporting Evidence: PMID:18363965 RAD18 complexed with RAD6B is recruited to stalled replication forks
GO:0005813 centrosome	IEA GO_REF:0000044	ACCEPT	Summary: PMID:15632077 provides experimental evidence that BRCTx (a RAD18-interacting protein) localizes to the centrosome, and the study showed RAD18 interaction with BRCTx. RAD18 centrosome localization is experimentally supported. Reason: Centrosome localization is supported by IDA evidence from PMID:15632077, validating the IEA annotation. Supporting Evidence: PMID:15632077 the BRCT domain of BRCTx is responsible for mediating its localization to the nucleus and centrosome in interphase cells
GO:0006281 DNA repair	IEA GO_REF:0000120	ACCEPT	Summary: RAD18 participates in DNA repair through its role in postreplication repair. While DNA damage tolerance (GO:0006301) is more precise for RAD18's primary function, DNA repair as a parent term is not incorrect. PMID:10884424 describes RAD18's role in postreplication repair. Reason: DNA repair is a broader term that encompasses RAD18's function. While DNA damage tolerance is more specific, this annotation is not incorrect. Supporting Evidence: PMID:10884424 Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens
GO:0006301 DNA damage tolerance	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. DNA damage tolerance is the core biological process for RAD18. Reason: Correct annotation, duplicative with IBA evidence but acceptable. Supporting Evidence: PMID:10884424 Dysfunction of human Rad18 results in defective postreplication repair
GO:0006513 protein monoubiquitination	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of IBA annotation. RAD18 catalyzes PCNA monoubiquitination. Reason: Correct annotation, duplicative with IBA evidence. Supporting Evidence: PMID:18363965 The SAP domain is also required for the efficient mono-ubiquitination of PCNA
GO:0006974 DNA damage response	IEA GO_REF:0000120	ACCEPT	Summary: RAD18 is involved in the cellular response to DNA damage, particularly at stalled replication forks. Multiple IDA annotations support this (PMID:22036607, PMID:25023518, PMID:25931565). Reason: DNA damage response is well-supported by multiple experimental studies. Supporting Evidence: PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	Summary: RAD18 contains a RING finger domain and a UBZ (ubiquitin-binding zinc finger) domain, both of which coordinate zinc ions. The RING domain is essential for E3 ligase activity. Reason: Zinc ion binding is structurally required for both the RING and UBZ domains. This is a valid molecular function annotation. Supporting Evidence: PMID:10884424 hRad18 protein binds to hHR6 protein through a conserved ring-finger motif
GO:0016740 transferase activity	IEA GO_REF:0000043	MODIFY	Summary: RAD18 has E3 ubiquitin ligase activity (EC 2.3.2.27), which is a type of transferase. However, this is a very general term. Reason: While technically correct, GO:0061630 (ubiquitin protein ligase activity) or GO:0004842 (ubiquitin-protein transferase activity) are more specific and informative. Proposed replacements: ubiquitin protein ligase activity
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: RAD18 binds zinc ions through its RING finger and UBZ domains. Metal ion binding is a parent term of zinc ion binding. Reason: Correct but redundant with zinc ion binding annotation. Both are valid.
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000120	ACCEPT	Summary: RAD18 is a RING-type E3 ubiquitin ligase (EC 2.3.2.27). It catalyzes ubiquitin transfer from E2 RAD6 to substrate PCNA. This is the core molecular function of RAD18. Reason: This is the primary molecular function annotation for RAD18 and accurately describes its enzymatic activity. Supporting Evidence: PMID:10884424 hRad18 protein binds to hHR6 protein through a conserved ring-finger motif PMID:10908344 stable hRAD18-HHR6A and hRAD18-HHR6B protein complexes were identified and purified
GO:0005515 protein binding	IPI PMID:18316726 Human HLTF functions as a ubiquitin ligase for proliferating...	REMOVE	Summary: This annotation reflects RAD18 interaction with HLTF (Q14527). The study examined HLTF's role in PCNA polyubiquitination and showed RAD18-HLTF interaction. Reason: Per curation guidelines, GO:0005515 (protein binding) is uninformative and should be replaced with more specific terms. The RAD18-HLTF interaction is functionally relevant to DNA damage tolerance pathway. Supporting Evidence: PMID:18316726 Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination.
GO:0005515 protein binding	IPI PMID:18719106 Polyubiquitination of proliferating cell nuclear antigen by ...	REMOVE	Summary: Another HLTF interaction annotation. HLTF and SHPRH are E3 ligases that interact with RAD18 for PCNA polyubiquitination. Reason: GO:0005515 is uninformative. The interaction with HLTF is relevant to RAD18's role in DNA damage tolerance but protein binding term lacks specificity. Supporting Evidence: PMID:18719106 Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks.
GO:0005515 protein binding	IPI PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protei...	REMOVE	Summary: High-throughput E2 interaction network study. Shows RAD18 interaction with UBE2A (P49459) and UBE2B (P63146), its E2 partners. Reason: The RAD6 interaction is important but captured by Rad6-Rad18 complex annotation. Protein binding is too general. Supporting Evidence: PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.
GO:0005515 protein binding	IPI PMID:21422291 E3 ligase Rad18 promotes monoubiquitination rather than ubiq...	REMOVE	Summary: Study on RAD18 promoting monoubiquitination rather than chain formation. Shows RAD18-UBE2B interaction. Reason: GO:0005515 is uninformative. The E2 interaction is captured by complex annotation. Supporting Evidence: PMID:21422291 E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6.
GO:0005515 protein binding	IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme...	REMOVE	Summary: Chromatin-related protein interaction study. Shows RAD18-UBE2A interaction. Reason: GO:0005515 is uninformative. High-throughput interactome data. Supporting Evidence: PMID:24981860 2014 Jun 26. Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Large-scale human interactome mapping. Shows RAD18 interaction with TAX1BP1 (Q86VP1). Reason: GO:0005515 is uninformative. High-throughput interactome data. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	REMOVE	Summary: Quantitative interactome study. Shows RAD18-UBE2A interaction. Reason: GO:0005515 is uninformative. Redundant with other E2 interaction annotations. Supporting Evidence: PMID:26496610 Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: Architecture of human interactome. Shows interactions with MAGEA3 (P43358) and UBE2B (P63146). Reason: GO:0005515 is uninformative. High-throughput interactome data. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Reference map of human binary interactome. Shows multiple interactions including SA1 (O14737), MAGEA3, GOLGA2, ORC2, DAZAP1, TAX1BP1, NAPB. Reason: GO:0005515 is uninformative. High-throughput interactome data. 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 ...	REMOVE	Summary: Neurodegenerative disease interactome study. Shows interactions with ATXN1 (P54253) and TARDBP (Q13148). Reason: GO:0005515 is uninformative. These interactions may not be functionally relevant to RAD18's core DNA damage tolerance function. 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...	REMOVE	Summary: Cell-specific interactome remodeling. Shows MAGEA3 and UBE2B interactions. Reason: GO:0005515 is uninformative. The UBE2B interaction is captured by complex annotation. 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:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Multimodal cell maps study. Shows MAGEA3 interaction. Reason: GO:0005515 is uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence data showing RAD18 localization in nucleoplasm. Consistent with RAD18's nuclear function in DNA damage tolerance. Reason: Nucleoplasm localization is consistent with RAD18's function at replication forks and DNA damage sites.
GO:0016604 nuclear body	IDA GO_REF:0000052	ACCEPT	Summary: HPA data showing RAD18 in nuclear bodies. RAD18 forms foci at DNA damage sites, consistent with this annotation. Reason: Nuclear body localization is consistent with RAD18's DNA damage-induced foci formation. Supporting Evidence: PMID:22036607 this interaction, mediated via highly conserved serine residues on the RAD18 C terminus, is required for BRCTx accumulation at DNA damage sites
GO:0016607 nuclear speck	IDA GO_REF:0000052	ACCEPT	Summary: HPA data showing RAD18 in nuclear specks. This may reflect RAD18 foci or storage/regulatory localization. Reason: Consistent with nuclear localization data from HPA.
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: RAD18 catalyzes ubiquitination of PCNA. This is a parent term of protein monoubiquitination. Reason: Correct but less specific than protein monoubiquitination. Both annotations are valid.
GO:0005515 protein binding	IPI PMID:35849344 LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damag...	REMOVE	Summary: LncRNA CTBP1-DT microprotein DDUP interaction study. Reason: GO:0005515 is uninformative. Supporting Evidence: PMID:35849344 LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.
GO:0005634 nucleus	IDA PMID:25023518 DNA damage-specific deubiquitination regulates Rad18 functio...	ACCEPT	Summary: Zeman et al. 2014 showed RAD18 nuclear localization and formation of nuclear foci after DNA damage. The study demonstrates wild-type RAD18 forms detergent-resistant nuclear foci after MMS, UV, or ionizing radiation treatment. Reason: Strong experimental evidence for nuclear localization. Core localization annotation. Supporting Evidence: PMID:25023518 Although wild-type Rad18 foci were observed after MMS treatment
GO:0006974 DNA damage response	IDA PMID:25023518 DNA damage-specific deubiquitination regulates Rad18 functio...	ACCEPT	Summary: Zeman et al. 2014 comprehensively demonstrated RAD18's role in DNA damage response. RAD18 is deubiquitinated after MMS/H2O2 treatment, enabling interaction with SHPRH for error-free bypass. Reason: Strong experimental support for RAD18's involvement in DNA damage response. Supporting Evidence: PMID:25023518 Upon exposure to MMS or H2O2, Rad18 is deubiquitinated, promoting a switch from Rad18•Ub–Rad18 complexes to Rad18–SHPRH complexes and error-free bypass of DNA lesions
GO:0042802 identical protein binding	IDA PMID:25023518 DNA damage-specific deubiquitination regulates Rad18 functio...	ACCEPT	Summary: Zeman et al. 2014 demonstrated RAD18 homodimerization/self-interaction. The ubiquitinated form of RAD18 (Rad18-Ub) preferentially binds to non-ubiquitinated RAD18, and this interaction modulates RAD18 activity. Reason: Self-interaction is experimentally demonstrated and functionally significant. This is more informative than generic protein binding. Supporting Evidence: PMID:25023518 Interestingly, Rad18•Ub also has a strong preference for binding to nonubiquitinated Rad18, suggesting that the ubiquitinated form may inhibit other Rad18 molecules in trans
GO:0051865 protein autoubiquitination	IDA PMID:25023518 DNA damage-specific deubiquitination regulates Rad18 functio...	ACCEPT	Summary: RAD18 undergoes autoubiquitination with its E2 partner RAD6. Zeman et al. 2014 showed that ~25% of RAD18 exists in monoubiquitinated form, and this is enhanced by RAD6 co-expression. Reason: Autoubiquitination is experimentally demonstrated and is an important regulatory mechanism for RAD18 activity. Supporting Evidence: PMID:25023518 Rad18 is monoubiquitinated in several different mammalian cell lines
GO:0005515 protein binding	IPI PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of ...	REMOVE	Summary: RAD18-BRCTx (Q8R3P9) interaction. BRCTx is a RAD18-interacting protein. Reason: GO:0005515 is uninformative. The RAD18-BRCTx interaction is functionally relevant but should be captured by more specific terms. Supporting Evidence: PMID:22036607 Epub 2011 Oct 28. RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage.
GO:0005634 nucleus	IDA PMID:15632077 BRCTx is a novel, highly conserved RAD18-interacting protein...	ACCEPT	Summary: Adams et al. 2005 showed BRCTx colocalizes with RAD18 in the nucleus. Reason: Confirms nuclear localization. Supporting Evidence: PMID:15632077 BRCTx binds to the C terminus of hRAD18 in yeast two-hybrid and immunoprecipitation assays and colocalizes with this protein in the nucleus
GO:0005634 nucleus	IDA PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of ...	ACCEPT	Summary: Liu et al. 2012 confirmed RAD18 nuclear localization during UV damage response. Reason: Confirms nuclear localization. Supporting Evidence: PMID:22036607 Epub 2011 Oct 28. RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage.
GO:0005813 centrosome	IDA PMID:15632077 BRCTx is a novel, highly conserved RAD18-interacting protein...	ACCEPT	Summary: Adams et al. 2005 showed BRCTx localizes to centrosome and interacts with RAD18. This suggests RAD18 may also localize to centrosome through BRCTx interaction. Reason: Centrosome localization is supported by experimental evidence. Supporting Evidence: PMID:15632077 the BRCT domain of BRCTx is responsible for mediating its localization to the nucleus and centrosome in interphase cells
GO:0006974 DNA damage response	IDA PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of ...	ACCEPT	Summary: Liu et al. 2012 demonstrated RAD18-BRCTx module is critical for UV-induced DNA damage repair. Reason: Strong experimental support for DNA damage response involvement. Supporting Evidence: PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of UV-induced DNA damage
GO:0042405 nuclear inclusion body	IDA PMID:22036607 RAD18-BRCTx interaction is required for efficient repair of ...	ACCEPT	Summary: Liu et al. 2012 showed RAD18 forms nuclear inclusion bodies during DNA damage. Reason: Specific localization during DNA damage response. Supporting Evidence: PMID:22036607 this interaction, mediated via highly conserved serine residues on the RAD18 C terminus, is required for BRCTx accumulation at DNA damage sites
GO:0044877 protein-containing complex binding	IPI PMID:25931565 DNA repair. Proteomics reveals dynamic assembly of repair co...	ACCEPT	Summary: Raschle et al. 2015 identified SLF1 (Q8IY18) and SLF2 (Q96SB8) as forming a complex with RAD18 that recruits SMC5/6 to DNA lesions. Reason: More informative than generic protein binding. RAD18 forms a complex with SLF1/SLF2 for SMC5/6 recruitment. Supporting Evidence: PMID:25931565 SLF1 and SLF2, which form a complex with RAD18 and together define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions
GO:0005515 protein binding	IPI PMID:25931565 DNA repair. Proteomics reveals dynamic assembly of repair co...	REMOVE	Summary: Same study as above, shows interactions with ANKRD17 (Q8IX21) and ELF1 (Q9BQI6). Reason: GO:0005515 is uninformative. The more specific protein-containing complex binding annotation captures the SLF1/SLF2 interaction. Supporting Evidence: PMID:25931565 Apr 30. DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links.
GO:0006974 DNA damage response	IDA PMID:25931565 DNA repair. Proteomics reveals dynamic assembly of repair co...	ACCEPT	Summary: Raschle et al. 2015 proteomics study of DNA repair during ICL bypass revealed RAD18's role in the DNA damage response. Reason: Strong experimental support from systematic proteomics study. Supporting Evidence: PMID:25931565 define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions
GO:0035861 site of double-strand break	IDA PMID:25931565 DNA repair. Proteomics reveals dynamic assembly of repair co...	ACCEPT	Summary: Raschle et al. 2015 showed RAD18 is recruited to DNA double-strand breaks as part of the repair complex assembly. Reason: Specific localization to DSB sites during repair. Supporting Evidence: PMID:25931565 Among numerous prospective DNA repair factors, we identified SLF1 and SLF2, which form a complex with RAD18 and together define a pathway that suppresses genome instability by recruiting the SMC5/6 cohesion complex to DNA lesions
GO:0051984 positive regulation of chromosome segregation	IMP PMID:25931565 DNA repair. Proteomics reveals dynamic assembly of repair co...	KEEP AS NON CORE	Summary: Raschle et al. 2015 showed RAD18-SLF1-SLF2 complex promotes genome stability, which includes proper chromosome segregation. Reason: This is a downstream consequence of RAD18's DNA damage tolerance function rather than a core function. Keep as non-core. Supporting Evidence: PMID:25931565 define a pathway that suppresses genome instability
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5652005	ACCEPT	Summary: Reactome annotation for RAD18:UBE2B complex binding to PCNA associated with damaged DNA. Reason: Consistent with nucleoplasm localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5652009	ACCEPT	Summary: Reactome annotation for RAD18:UBE2B monoubiquitinating PCNA. Reason: Consistent with nucleoplasm localization for PCNA ubiquitination.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8943003	ACCEPT	Summary: Reactome annotation for SHPRH polyubiquitinating monoubiquitinated PCNA (RAD18 participates). Reason: Consistent with nucleoplasm localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8943007	ACCEPT	Summary: Reactome annotation for SHPRH binding monoUb-PCNA with RAD6:RAD18. Reason: Consistent with nucleoplasm localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8943040	ACCEPT	Summary: Reactome annotation for HLTF polyubiquitinating monoubiquitinated PCNA. Reason: Consistent with nucleoplasm localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8943041	ACCEPT	Summary: Reactome annotation for HLTF binding monoUb-PCNA with RAD6:RAD18. Reason: Consistent with nucleoplasm localization.
GO:0031593 polyubiquitin modification-dependent protein binding	IDA PMID:22742833 Tandem protein interaction modules organize the ubiquitin-de...	ACCEPT	Summary: Panier et al. 2012 showed RAD18 accumulates at DSB sites through ubiquitin-binding domains (UBZ). RAD18's UBZ domain recognizes ubiquitinated chromatin for recruitment to damage sites. Reason: This is a specific molecular function that describes how RAD18 is recruited to damage sites via ubiquitin recognition. More informative than generic protein binding. Supporting Evidence: PMID:22742833 RNF168, its paralog RNF169, RAD18, and the BRCA1-interacting RAP80 protein accumulate at DSB sites through the use of bipartite modules composed of UBDs juxtaposed to peptide motifs that provide specificity
GO:0005515 protein binding	IPI PMID:22681887 Spartan/C1orf124, a reader of PCNA ubiquitylation and a regu...	REMOVE	Summary: Spartan/C1orf124 (Q9H040) interaction - a reader of PCNA ubiquitylation. Reason: GO:0005515 is uninformative. Supporting Evidence: PMID:22681887 Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response.
GO:0005515 protein binding	IPI PMID:21659603 A DNA damage response screen identifies RHINO, a 9-1-1 and T...	REMOVE	Summary: RHINO (Q9BSD3) interaction study. Reason: GO:0005515 is uninformative. Supporting Evidence: PMID:21659603 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling.
GO:0000403 Y-form DNA binding	IDA PMID:18363965 Recognition of forked and single-stranded DNA structures by ...	ACCEPT	Summary: Tsuji et al. 2008 directly demonstrated that RAD18-RAD6B complex preferentially binds to forked (Y-form) DNA structures at stalled replication forks. Reason: This is a highly specific and experimentally validated molecular function. Y-form DNA binding is central to RAD18's recruitment to stalled forks. Supporting Evidence: PMID:18363965 Human RAD18 complexed with RAD6B protein preferentially binds to forked and single-stranded DNA (ssDNA) structures, which are known to be localized at stalled replication forks
GO:0005657 replication fork	IDA PMID:18363965 Recognition of forked and single-stranded DNA structures by ...	ACCEPT	Summary: Tsuji et al. 2008 demonstrated RAD18-RAD6B recruitment to stalled replication forks via recognition of forked and ssDNA structures. Reason: Replication fork localization is central to RAD18's function in DNA damage tolerance. Supporting Evidence: PMID:18363965 RAD18 complexed with RAD6B is recruited to stalled replication forks via interactions with forked DNA or long ssDNA structures
GO:0031625 ubiquitin protein ligase binding	IPI PMID:18363965 Recognition of forked and single-stranded DNA structures by ...	ACCEPT	Summary: RAD18 binds to its E2 partner UBE2B (P63146/RAD6B). This is the E2 that provides ubiquitin for PCNA monoubiquitination. Reason: Binding to E2 ubiquitin-conjugating enzyme is essential for E3 ligase function. This is more specific than generic protein binding. Supporting Evidence: PMID:18363965 RAD18 complexed with RAD6B protein
GO:0031625 ubiquitin protein ligase binding	IPI PMID:10908344 The human RAD18 gene product interacts with HHR6A and HHR6B.	ACCEPT	Summary: Xin et al. 2000 demonstrated human RAD18 interacts with both HHR6A (UBE2A/P49459) and HHR6B (UBE2B/P63146), forming stable complexes. Reason: E2 binding is essential for RAD18's E3 ligase function. Supporting Evidence: PMID:10908344 Human RAD18 protein (hRAD18) was found to interact with HHR6A and HHR6B
GO:0003684 damaged DNA binding	NAS PMID:10884424 Dysfunction of human Rad18 results in defective postreplicat...	MODIFY	Summary: Tateishi et al. 2000 characterized human RAD18 as involved in postreplication repair of damaged DNA. While not directly demonstrating damaged DNA binding, the function implies recognition of damage-associated structures. Reason: NAS evidence is weak. The more specific GO:0000403 (Y-form DNA binding) is supported by IDA evidence from PMID:18363965. RAD18 binds fork/ssDNA structures rather than damaged bases directly. Proposed replacements: Y-form DNA binding Supporting Evidence: PMID:10884424 Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens.
GO:0005634 nucleus	NAS PMID:10884424 Dysfunction of human Rad18 results in defective postreplicat...	ACCEPT	Summary: Early characterization paper. Nuclear localization is well-supported by later IDA evidence. Reason: Consistent with IDA evidence from multiple studies. Supporting Evidence: PMID:10884424 Dysfunction of human Rad18 results in defective postreplication repair and hypersensitivity to multiple mutagens.
GO:0006281 DNA repair	NAS PMID:10884424 Dysfunction of human Rad18 results in defective postreplicat...	ACCEPT	Summary: Tateishi et al. 2000 showed dysfunction of RAD18 results in defective postreplication repair. DNA repair is accurate but DNA damage tolerance (GO:0006301) is more specific. Reason: DNA repair as a parent term is not incorrect, even though DNA damage tolerance is more specific. Supporting Evidence: PMID:10884424 Dysfunction of human Rad18 results in defective postreplication repair

Gene Description

Existing Annotations Review

Core Functions

RAD18 is a RING-type E3 ubiquitin ligase (EC 2.3.2.27) that, with its E2 partner RAD6 (UBE2A/UBE2B), catalyzes monoubiquitination of PCNA at Lys164. Core enzymatic function supported by multiple studies (PMID:10884424, PMID:18363965, PMID:25023518).

RAD18-RAD6B complex preferentially binds forked and ssDNA structures at stalled replication forks. The SAP domain is essential for DNA binding and fork recruitment. Directly demonstrated by PMID:18363965.

References

Deep Research

Cyberian

Falcon

OpenAI

📄 View Raw YAML