MMS19 is a key component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) targeting complex, functioning as a HEAT-repeat scaffold protein that mediates the delivery of [4Fe-4S] clusters to cytosolic and nuclear target proteins. MMS19 partners with CIAO1, CIAO2B/FAM96B, and CIAO3/IOP1 in the CIA targeting complex, serving as an adapter between early-acting CIA components and specific Fe-S client proteins involved in DNA metabolism and genomic integrity. Key client proteins include XPD/ERCC2 (nucleotide excision repair and TFIIH component), FANCJ/BRIP1 (Fanconi anemia helicase), RTEL1 (telomere maintenance helicase), and DNA polymerases. Fe-S cluster insertion occurs in the cytoplasm prior to nuclear import and assembly of target proteins into functional complexes. MMS19 also participates in the MMXD complex (with XPD, MIP18, CIAO1) that localizes to the mitotic spindle and is required for proper chromosome segregation. Loss of MMS19 leads to instability of Fe-S client proteins, sensitivity to DNA damage, and defects in DNA replication and repair.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0097361 cytosolic [4Fe-4S] assembly targeting complex | IBA GO_REF:0000033 | ACCEPT | Summary: MMS19 is a core component of the cytosolic [4Fe-4S] assembly targeting complex (CIA targeting complex/CTC). This annotation is phylogenetically inferred and strongly supported by experimental evidence from multiple studies showing MMS19 forms a complex with CIAO1, CIAO2B/MIP18, and CIAO3/IOP1 (PMID:22678361, PMID:22678362, PMID:23585563). Reason: MMS19 is established as the central scaffold of the CIA targeting complex. Multiple independent studies using co-immunoprecipitation and mass spectrometry have demonstrated that MMS19 forms tight complexes with CIAO1, CIAO2B, and CIAO3 to facilitate Fe-S cluster transfer to target proteins (PMID:22678361, PMID:22678362, PMID:23585563). Supporting Evidence: PMID:22678361 we demonstrate that MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18 PMID:22678362 MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins PMID:23585563 Here, we show that MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex file:human/MMS19/MMS19-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0051604 protein maturation | IBA GO_REF:0000033 | ACCEPT | Summary: MMS19 is essential for maturation of Fe-S containing proteins by facilitating Fe-S cluster insertion. This phylogenetically inferred annotation is accurate but could be more specific. Reason: MMS19's primary function is to mediate protein maturation by inserting Fe-S clusters into apoproteins. This is the defining biochemical role of the CIA targeting complex. However, a more specific term such as "iron-sulfur cluster assembly" would be more informative. Supporting Evidence: PMID:22678362 MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins involved in methionine biosynthesis, DNA replication, DNA repair, and telomere maintenance |
| GO:0071817 MMXD complex | IBA GO_REF:0000033 | ACCEPT | Summary: MMS19 is a component of the MMXD complex (MMS19-MIP18-XPD complex), a TFIIH-independent complex containing XPD that localizes to the mitotic spindle and functions in chromosome segregation. This phylogenetic annotation is supported by direct experimental evidence. Reason: The MMXD complex was discovered in 2010 and contains MMS19, MIP18/FAM96B, XPD/ERCC2, CIAO1, and ANT2. MMS19 is essential for this complex's function in chromosome segregation (PMID:20797633). Supporting Evidence: PMID:20797633 We found a XPD protein complex containing MMS19... it included FAM96B (now designated MIP18), Ciao1, and ANT2. MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization of MMS19 is inferred from UniProt subcellular location annotation. This is supported by IDA evidence from PMID:20797633. Reason: While MMS19's primary function occurs in the cytoplasm where Fe-S cluster transfer takes place, nuclear localization has been experimentally demonstrated (PMID:20797633, PMID:11071939). The nuclear pool may participate in MMXD complex functions. Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosome localization is inferred from UniProt. MMS19 localizes to centrosomes during mitosis, particularly during prophase. Reason: Centrosomal localization during mitosis is documented in the UniProt entry based on experimental evidence (PMID:29848660). MMS19 is enriched on centrosomes during prophase as part of its role in facilitating Fe-S cluster delivery to mitotic proteins like KIF4A. |
| GO:0005819 spindle | IEA GO_REF:0000044 | ACCEPT | Summary: Spindle localization is inferred from UniProt and supported by direct experimental evidence showing MMS19 localizes to mitotic spindles. Reason: MMS19 localizes to the mitotic spindle as part of the MMXD complex, where it functions in chromosome segregation. This has been directly demonstrated (PMID:20797633). Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis |
| GO:0006281 DNA repair | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: MMS19 indirectly supports DNA repair by enabling maturation of Fe-S-containing DNA repair proteins including XPD (NER), FANCJ (crosslink repair), and other helicases. Reason: While MMS19 is critical for DNA repair by maturing Fe-S DNA repair proteins, it does not directly participate in the DNA repair reaction. Its role is upstream - ensuring that repair proteins receive their essential Fe-S cofactors. This is a secondary consequence of its primary function in Fe-S cluster delivery. Supporting Evidence: PMID:22678362 MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins involved in methionine biosynthesis, DNA replication, DNA repair, and telomere maintenance PMID:22678361 In the absence of MMS19, a failure to transfer Fe-S clusters to target proteins is associated with Fe-S protein instability |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: MMS19 indirectly supports transcription by maturing XPD, an Fe-S helicase that is a component of the TFIIH general transcription factor. Reason: MMS19 is not a direct transcription factor or core transcription machinery component. Its role in transcription is indirect - it matures XPD which is incorporated into TFIIH. This is a downstream consequence of its Fe-S cluster delivery function. Supporting Evidence: PMID:11279242 hMMS19 stimulates the AF-1 activity of ERalpha, but not the AF-2 activity, suggesting that hMMS19 may be an AF-1-specific transcriptional coactivator PMID:11071939 Co-immunoprecipitation experiments revealed that hMMS19 directly interacts with the XPB and XPD subunits of NER-transcription factor TFIIH |
| GO:0006974 DNA damage response | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: MMS19 supports DNA damage response indirectly by maturing Fe-S proteins involved in DNA damage sensing and repair. Reason: MMS19's role in DNA damage response is indirect, mediated through its function in maturing Fe-S proteins that participate in damage response pathways. MMS19 mutants show sensitivity to DNA damaging agents due to failure to mature repair proteins. Supporting Evidence: PMID:22678362 The function of MMS19 in the maturation of crucial components of DNA metabolism may explain the sensitivity of MMS19 mutants to DNA damage |
| GO:0007059 chromosome segregation | IEA GO_REF:0000043 | ACCEPT | Summary: MMS19 participates in chromosome segregation through the MMXD complex. Knockdown of MMS19 causes improper chromosome segregation. Reason: MMS19 is a component of the MMXD complex which localizes to the mitotic spindle and is required for proper chromosome segregation. This represents a core function beyond just Fe-S protein maturation (PMID:20797633). Supporting Evidence: PMID:20797633 The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to improper chromosome segregation and the accumulation of nuclei with abnormal shapes |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: This annotation is logically inferred from the transcription coactivator activity annotation. MMS19 can act as a coactivator for estrogen receptor-mediated transcription. Reason: While MMS19 has been shown to enhance ER-mediated transcription (PMID:11279242), this is likely a secondary function related to its role in TFIIH complex maturation rather than a direct transcriptional coactivator function. This represents a specialized context rather than a core function. Supporting Evidence: PMID:11279242 In contrast, over expression of the full-length hMMS19 enhances ER-mediated transcriptional activation |
| GO:0051604 protein maturation | IEA GO_REF:0000002 | ACCEPT | Summary: Protein maturation role inferred from InterPro MMS19 domain annotation. This is correct but general - MMS19 specifically matures Fe-S proteins. Reason: This IEA annotation from InterPro correctly identifies the protein maturation function of MMS19. While duplicative with other annotations, it provides additional computational evidence supporting the experimentally validated function. |
| GO:0005515 protein binding | IPI PMID:17314511 Large-scale identification of c-MYC-associated proteins usin... | MARK AS OVER ANNOTATED | Summary: Protein binding to c-MYC detected in high-throughput TAP/MudPIT screen. The biological significance is unclear. Reason: This is from a large-scale protein interaction study. While the interaction may be real, "protein binding" is uninformative and there is no established functional relationship between MMS19 and c-MYC. More specific molecular function terms are needed. Supporting Evidence: PMID:17314511 Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | MODIFY | Summary: Protein binding to CIAO1 detected by mass spectrometry. This interaction is functionally relevant as CIAO1 is a core CIA targeting complex component. Reason: While the interaction with CIAO1 is valid and important, "protein binding" is too vague. This should be annotated with a more specific term reflecting the functional relationship within the CIA targeting complex. Proposed replacements: cytosolic [4Fe-4S] assembly targeting complex Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO1 from next-generation sequencing interactome study. Reason: Duplicative with other CIAO1 interaction annotations. The generic "protein binding" term is uninformative when the specific functional complex (CIA targeting complex) is known. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets. |
| GO:0005515 protein binding | IPI PMID:23585563 IOP1 protein is an external component of the human cytosolic... | MODIFY | Summary: Multiple protein binding interactions detected - with CIAO1, XPD/ERCC2, BRIP1, CIAO3, RTEL1, and CIAO2B. These are all functionally relevant CIA complex or client interactions. Reason: These interactions are important and verified by low-throughput methods, but "protein binding" is too generic. The interactions with CIAO1, CIAO2B, CIAO3 represent CIA complex formation, while interactions with XPD, BRIP1, RTEL1 represent client binding for Fe-S cluster delivery. Proposed replacements: cytosolic [4Fe-4S] assembly targeting complex Supporting Evidence: PMID:23585563 Epub 2013 Apr 12. IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO1 from chromatin-related protein interaction study. Reason: Duplicative with other CIAO1 interaction annotations. The CIAO1 interaction is well established through other studies and the generic "protein binding" is uninformative. 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:28178521 The CIA Targeting Complex Is Highly Regulated and Provides T... | MODIFY | Summary: Protein binding to CIAO1, XPD/ERCC2, RTEL1, and CIAO2B from a study characterizing the CIA targeting complex client binding sites. Reason: This study (Stehling et al. 2017) provides detailed mechanistic understanding of client binding, but "protein binding" is too generic. The interactions should be captured through the complex annotation (GO:0097361). Proposed replacements: cytosolic [4Fe-4S] assembly targeting complex Supporting Evidence: PMID:28178521 The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO1 and CIAO2B from human interactome architecture study. Reason: Large-scale interactome study. These interactions are established but "protein binding" is uninformative when the functional complex (CIA targeting complex) is known. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO1 and CIAO2B from dual proteome-scale interactome study. Reason: High-throughput study confirming known interactions. The generic "protein binding" term adds no functional insight beyond what is captured by CIA complex annotations. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | ACCEPT | Summary: Enzyme binding inferred from mouse ortholog. MMS19 does bind to enzymes (Fe-S client proteins like XPD helicase), but this term is still quite general. Reason: While "enzyme binding" is somewhat general, it is more informative than "protein binding" and correctly reflects MMS19's function of binding to Fe-S enzymes for cluster delivery. Client proteins include helicases (XPD, FANCJ, RTEL1) and polymerases. |
| GO:0097361 cytosolic [4Fe-4S] assembly targeting complex | IEA GO_REF:0000120 | ACCEPT | Summary: CIA targeting complex membership inferred by combined automated annotation methods. Reason: This is correct and supported by experimental evidence. Duplicative with IDA and IBA annotations but provides additional computational support. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization determined by HPA immunofluorescence data curation. Reason: Nucleoplasm localization is consistent with MMS19's role in maturing nuclear Fe-S proteins and participation in MMXD complex. While cytoplasm is the primary site of action, nuclear localization is also observed. |
| GO:0051604 protein maturation | IMP PMID:22678361 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA ... | ACCEPT | Summary: Protein maturation function demonstrated by mutant phenotype - MMS19 knockdown leads to instability of Fe-S client proteins. Reason: This is a core function of MMS19. The study demonstrated that in the absence of MMS19, Fe-S cluster transfer fails and target proteins become unstable (PMID:22678361). Supporting Evidence: PMID:22678361 In the absence of MMS19, a failure to transfer Fe-S clusters to target proteins is associated with Fe-S protein instability |
| GO:0051604 protein maturation | IDA PMID:29225034 Cytosolic Iron-Sulfur Assembly Is Evolutionarily Tuned by a ... | ACCEPT | Summary: Protein maturation function demonstrated by direct assay - study showed MMS19 is required for Fe-S cluster incorporation into DNA repair enzymes. Reason: This study demonstrated that overexpression or knockout of MAGE-F1 (which regulates MMS19 levels) altered Fe-S incorporation into MMS19-dependent DNA repair enzymes, confirming MMS19's essential role in protein maturation through Fe-S cluster delivery. Supporting Evidence: PMID:29225034 Overexpression or knockout of MAGE-F1 altered Fe-S incorporation into MMS19-dependent DNA repair enzymes |
| GO:0005737 cytoplasm | NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic... | ACCEPT | Summary: Cytoplasmic localization from ComplexPortal annotation based on PMID:23585563. Reason: Cytoplasm is the primary site of MMS19 function where Fe-S cluster transfer to client proteins occurs. This is well established by multiple studies. Supporting Evidence: PMID:23585563 Here, we show that MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex |
| GO:0016226 iron-sulfur cluster assembly | NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic... | ACCEPT | Summary: Iron-sulfur cluster assembly process annotation from ComplexPortal. MMS19 functions in the late stages of cytosolic Fe-S protein assembly. Reason: This correctly captures MMS19's core function in the CIA pathway. MMS19 is part of the targeting complex that delivers Fe-S clusters to client proteins. Supporting Evidence: PMID:23585563 Recent studies have revealed that MMS19 and cytosolic iron-sulfur cluster assembly (CIA) factors form a complex and have central roles in CIA pathway |
| GO:0005515 protein binding | IPI PMID:30742009 Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA ... | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO2B. The study found CCDC117 interacts with MMS19 indirectly through the CIA complex. Reason: The CIAO2B interaction is established but "protein binding" is uninformative. The functional complex (CIA targeting complex) is already annotated. Supporting Evidence: PMID:30742009 Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation. |
| GO:0097361 cytosolic [4Fe-4S] assembly targeting complex | IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic... | ACCEPT | Summary: CIA targeting complex membership demonstrated by co-immunoprecipitation and biochemical characterization showing MMS19 forms core complex with CIAO1, MIP18, and external component IOP1. Reason: This is strong experimental evidence for MMS19's core function as a CIA targeting complex component. The study provided detailed characterization of the complex architecture. Supporting Evidence: PMID:23585563 Here, we show that MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex |
| GO:0005515 protein binding | IPI PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas... | MARK AS OVER ANNOTATED | Summary: Protein binding to CIAO1 and CIAO2B from study characterizing CIA2A and CIA2B functions. Reason: Valid interactions but "protein binding" is uninformative. The functional complex annotation (GO:0097361) provides better context. Supporting Evidence: PMID:23891004 2013 Jul 25. Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | UNDECIDED | Summary: Membrane localization from high-throughput direct assay (NK cell membrane proteome study). Reason: MMS19 is primarily cytoplasmic and nuclear. Membrane association is unexpected and may represent contamination or transient association in this high-throughput proteomics study. This contradicts the established cytoplasmic/nuclear localization from focused studies. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0005737 cytoplasm | IDA PMID:22678361 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA ... | ACCEPT | Summary: Cytoplasmic localization directly demonstrated by Gari et al. 2012. Reason: The cytoplasm is where MMS19 executes its primary function of Fe-S cluster delivery to client proteins. This is well-established experimental evidence. Supporting Evidence: PMID:22678361 Cytoplasmic MMS19 also binds to multiple nuclear Fe-S proteins involved in DNA metabolism |
| GO:0097361 cytosolic [4Fe-4S] assembly targeting complex | IDA PMID:22678361 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA ... | ACCEPT | Summary: CIA targeting complex membership demonstrated by co-immunoprecipitation showing MMS19 forms complex with CIA proteins CIAO1, IOP1, and MIP18. Reason: This is primary experimental evidence establishing MMS19 as a CIA targeting complex component. Supporting Evidence: PMID:22678361 we demonstrate that MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18 |
| GO:0097361 cytosolic [4Fe-4S] assembly targeting complex | IDA PMID:22678362 MMS19 assembles iron-sulfur proteins required for DNA metabo... | ACCEPT | Summary: CIA targeting complex membership demonstrated by Stehling et al. 2012, which identified MMS19 as a member of CIA machinery functioning in the targeting complex. Reason: This landmark study identified MMS19 as part of the CIA targeting complex that facilitates Fe-S cluster insertion into DNA metabolism proteins. Supporting Evidence: PMID:22678362 we identify MMS19 as a member of the cytosolic iron-sulfur protein assembly (CIA) machinery. MMS19 functions as part of the CIA targeting complex |
| GO:0005515 protein binding | IPI PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved... | MODIFY | Summary: Protein binding to CIAO2B from the MMXD complex study. Reason: This interaction is functionally important for MMXD complex formation but "protein binding" is too generic. The MMXD complex annotation (GO:0071817) better captures this. Proposed replacements: MMXD complex Supporting Evidence: PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation. |
| GO:0005634 nucleus | IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved... | ACCEPT | Summary: Nuclear localization demonstrated by immunofluorescence in the MMXD complex study. Reason: Nuclear localization is experimentally validated and consistent with MMS19's role in the MMXD complex and maturation of nuclear Fe-S proteins. Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis |
| GO:0005737 cytoplasm | IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved... | ACCEPT | Summary: Cytoplasmic localization demonstrated in the MMXD complex study. Reason: Cytoplasm is the primary site of MMS19 function. Experimental validation from multiple independent studies. Supporting Evidence: PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation. |
| GO:0005819 spindle | IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved... | ACCEPT | Summary: Spindle localization directly demonstrated by immunofluorescence during mitosis. Reason: MMS19 localizes to the mitotic spindle as part of the MMXD complex. This is required for its role in chromosome segregation. Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis |
| GO:0071817 MMXD complex | IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved... | ACCEPT | Summary: MMXD complex membership directly demonstrated. MMS19 was identified as a core component of this TFIIH-independent XPD-containing complex. Reason: This study discovered and characterized the MMXD complex, showing MMS19 is an essential component required for chromosome segregation. Supporting Evidence: PMID:20797633 the MMS19-XPD protein complex, now designated MMXD (MMS19-MIP18-XPD), is required for proper chromosome segregation |
| GO:0003713 transcription coactivator activity | IMP PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | KEEP AS NON CORE | Summary: Transcription coactivator activity demonstrated by mutant phenotype - overexpression of hMMS19 enhanced ER-mediated transcription while dominant negative construct inhibited it. Reason: While experimentally validated, this transcriptional coactivator activity likely represents an indirect effect of MMS19's role in maturing TFIIH components (XPD, XPB) rather than direct coactivator function. This may be a secondary consequence of Fe-S protein maturation. Supporting Evidence: PMID:11279242 In contrast, over expression of the full-length hMMS19 enhances ER-mediated transcriptional activation |
| GO:0005675 transcription factor TFIIH holo complex | NAS PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | REMOVE | Summary: TFIIH complex association inferred from interaction with XPD and XPB, which are TFIIH components. Reason: MMS19 is not a bona fide component of the TFIIH holo complex. While it interacts with XPD and XPB, this interaction is for Fe-S cluster delivery before these proteins are incorporated into TFIIH. MMS19 functions in the cytoplasm whereas TFIIH is a nuclear transcription factor complex. The CIA targeting complex is the appropriate complex annotation. Supporting Evidence: PMID:11279242 2001 Mar 28. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor. PMID:22678361 Jun 7. MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism. PMID:22678362 Jun 7. MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. |
| GO:0030159 signaling receptor complex adaptor activity | NAS PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | REMOVE | Summary: Signaling receptor complex adaptor activity inferred from the estrogen receptor coactivator study. Reason: This annotation appears to be a misinterpretation of MMS19's function. The 2001 study interpreted MMS19 as an adapter between ER and TFIIH, but subsequent work (2012 onward) established that MMS19's primary function is in Fe-S cluster delivery. Its role in ER signaling is indirect through XPD/TFIIH maturation, not as a classical signaling adapter. Supporting Evidence: PMID:11279242 2001 Mar 28. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor. |
| GO:0030331 nuclear estrogen receptor binding | IPI PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | KEEP AS NON CORE | Summary: Estrogen receptor binding demonstrated by co-immunoprecipitation. MMS19 interacted with ER in ligand-independent manner. Reason: While experimentally validated, this ER binding may be related to MMS19's indirect role in supporting ER-mediated transcription through TFIIH maturation. This is not a core function of MMS19. Supporting Evidence: PMID:11279242 the human MMS19 also interacts with estrogen receptors in a ligand-independent manner |
| GO:0030674 protein-macromolecule adaptor activity | NAS PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | MODIFY | Summary: Adaptor activity inferred from the ER coactivator study, suggesting MMS19 bridges ER and TFIIH. Reason: MMS19 does function as an adaptor, but the current understanding is that it adapts between early CIA components and Fe-S client proteins, not between ER and TFIIH. The annotation should reflect its established adaptor function in Fe-S cluster delivery. Proposed replacements: cytosolic [4Fe-4S] assembly targeting complex Supporting Evidence: PMID:22678362 MMS19 thus serves as an adapter between early-acting CIA components and a subset of cellular iron-sulfur proteins PMID:11279242 2001 Mar 28. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor. |
| GO:0005515 protein binding | IPI PMID:11279242 The human homologue of the yeast DNA repair and TFIIH regula... | MARK AS OVER ANNOTATED | Summary: Protein binding to RAC3/NCOA3 demonstrated in the ER coactivator study. Reason: While this interaction was demonstrated, "protein binding" is uninformative. The functional significance of the RAC3 interaction is unclear in light of subsequent understanding of MMS19's primary role in Fe-S cluster delivery. Supporting Evidence: PMID:11279242 2001 Mar 28. The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor. |
| GO:0005634 nucleus | TAS PMID:11071939 Cloning of a human homolog of the yeast nucleotide excision ... | ACCEPT | Summary: Nuclear localization from early characterization study. "Traceable Author Statement" evidence from the paper that cloned human MMS19. Reason: Nuclear localization was reported in the original cloning paper and is consistent with MMS19's role in the MMXD complex and maturation of nuclear Fe-S proteins. Supporting Evidence: PMID:11071939 The expression profile and nuclear location are consistent with a repair function |
| GO:0060090 molecular adaptor activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:20797633 The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to improper chromosome segregation and the accumulation of nuclei with abnormal shapes |
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Download this section (compressed HTML)Q: How does MMS19 recognize and select specific Fe-S client proteins from the proteome?
Q: What is the structural basis for MMS19's interaction with different client proteins?
Q: Is MMS19's role in chromosome segregation (via MMXD) entirely dependent on XPD Fe-S cluster loading, or does it have additional functions?
Experiment: Cryo-EM structure of MMS19 bound to different client proteins to understand substrate recognition
Experiment: Proteomics to identify the complete set of MMS19-dependent Fe-S client proteins in human cells
Experiment: Time-course experiments to determine the order of events in CIA targeting complex assembly and client engagement
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