MMS19

UniProt ID: Q96T76
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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.
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.
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).
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.
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

Core Functions

MMS19 is the central scaffold component of the CIA targeting complex, functioning as an adaptor between early-acting CIA components and Fe-S client proteins. MMS19's HEAT-repeat architecture provides the binding platform for both complex partners (CIAO1, CIAO2B, CIAO3) and client Fe-S proteins (XPD, FANCJ, RTEL1, polymerases). Multiple studies using co-IP and mass spectrometry have demonstrated this complex formation (PMID:22678361, PMID:22678362, PMID:23585563).

Molecular Function:
molecular adaptor activity
Directly Involved In:
iron-sulfur cluster assembly protein maturation
Cellular Locations:
cytoplasm
In Complex:
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:23585563
    MMS19, MIP18, and CIAO1 form a tight 'core' complex

MMS19 participates in chromosome segregation through the MMXD complex (MMS19-MIP18-XPD). This complex localizes to the mitotic spindle and is required for proper chromosome segregation. MMS19 knockdown causes improper chromosome segregation and abnormal nuclear morphology.

Molecular Function:
molecular adaptor activity
Directly Involved In:
chromosome segregation
Cellular Locations:
spindle centrosome
In Complex:
MMXD complex
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

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:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
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:0000108
Automatic assignment of GO terms using logical inference, based on inter-ontology links
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:11071939
Cloning of a human homolog of the yeast nucleotide excision repair gene MMS19 and interaction with transcription repair factor TFIIH via the XPB and XPD helicases.
  • First cloning of human MMS19, showing interaction with XPB and XPD subunits of TFIIH
  • Established nuclear localization and ubiquitous expression
PMID:11279242
The human homologue of the yeast DNA repair and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen receptor.
  • MMS19 interacts with RAC3/NCOA3 and estrogen receptor
  • Acts as AF-1-specific coactivator enhancing ER-mediated transcription
  • Early interpretation as transcription adapter (superseded by Fe-S cluster delivery model)
PMID:17314511
Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.
PMID:17353931
Large-scale mapping of human protein-protein interactions by mass spectrometry.
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20797633
MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation.
  • Discovery of MMXD complex containing MMS19, MIP18, XPD, CIAO1, and ANT2
  • MMXD localizes to mitotic spindle during mitosis
  • MMS19 knockdown causes improper chromosome segregation
  • MMXD is distinct from TFIIH
PMID:21516116
Next-generation sequencing to generate interactome datasets.
PMID:22678361
MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.
  • MMS19 forms complex with CIA proteins CIAO1, IOP1, and MIP18
  • Cytoplasmic MMS19 binds multiple nuclear Fe-S proteins involved in DNA metabolism
  • MMS19 functions as platform for Fe-S cluster transfer to DNA repair proteins
  • MMS19 knockout mice die during preimplantation
PMID:22678362
MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity.
  • MMS19 identified as member of CIA machinery
  • Functions as adapter between early-acting CIA components and Fe-S client proteins
  • Client proteins include those for DNA replication, repair, and telomere maintenance
  • Explains sensitivity of MMS19 mutants to DNA damage
PMID:23585563
IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery.
  • MMS19, MIP18, and CIAO1 form tight core complex
  • IOP1 is external component
  • MMS19 interacts directly with target proteins
  • MIP18 bridges MMS19 and CIAO1
PMID:23891004
Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins.
PMID:24981860
Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
PMID:28178521
The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:29225034
Cytosolic Iron-Sulfur Assembly Is Evolutionarily Tuned by a Cancer-Amplified Ubiquitin Ligase.
  • MAGE-F1-NSE1 E3 ligase regulates CIA pathway through MMS19 ubiquitination
  • MMS19 degradation affects Fe-S incorporation into DNA repair enzymes
  • MAGE-F1 amplification in cancer increases mutational burden
PMID:30742009
Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
file:human/MMS19/MMS19-deep-research-falcon.md
Deep research report on MMS19

Suggested Questions for Experts

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?

Suggested Experiments

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

Tags

iron-sulfur-cluster-biogenesis

πŸ“š Additional Documentation

Deep Research Falcon

(MMS19-deep-research-falcon.md)

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organism: human
gene_id: MMS19
gene_symbol: MMS19
uniprot_accession: Q96T76
protein_description: 'RecName: Full=MMS19 nucleotide excision repair protein homolog
{ECO:0000305}; Short=hMMS19; AltName: Full=MET18 homolog; AltName: Full=MMS19-like
protein;'
gene_info: Name=MMS19 {ECO:0000312|HGNC:HGNC:13824}; Synonyms=MMS19L;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the MET18/MMS19 family. .
protein_domains: ARM-like. (IPR011989); ARM-type_fold. (IPR016024); MMS19. (IPR039920);
MMS19_C. (IPR024687); MMS19_N. (IPR029240)
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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: Q96T76
  • Protein Description: RecName: Full=MMS19 nucleotide excision repair protein homolog {ECO:0000305}; Short=hMMS19; AltName: Full=MET18 homolog; AltName: Full=MMS19-like protein;
  • Gene Information: Name=MMS19 {ECO:0000312|HGNC:HGNC:13824}; Synonyms=MMS19L;
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the MET18/MMS19 family. .
  • Key Domains: ARM-like. (IPR011989); ARM-type_fold. (IPR016024); MMS19. (IPR039920); MMS19_C. (IPR024687); MMS19_N. (IPR029240)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "MMS19" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. 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 'MMS19' 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 MMS19 (gene ID: MMS19, UniProt: Q96T76) 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: Q96T76
  • Protein Description: RecName: Full=MMS19 nucleotide excision repair protein homolog {ECO:0000305}; Short=hMMS19; AltName: Full=MET18 homolog; AltName: Full=MMS19-like protein;
  • Gene Information: Name=MMS19 {ECO:0000312|HGNC:HGNC:13824}; Synonyms=MMS19L;
  • Organism (full): Homo sapiens (Human).
  • Protein Family: Belongs to the MET18/MMS19 family. .
  • Key Domains: ARM-like. (IPR011989); ARM-type_fold. (IPR016024); MMS19. (IPR039920); MMS19_C. (IPR024687); MMS19_N. (IPR029240)

MANDATORY VERIFICATION STEPS:

  1. Check if the gene symbol "MMS19" matches the protein description above
  2. Verify the organism is correct: Homo sapiens (Human).
  3. Check if protein family/domains align with what you find in literature
  4. 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 'MMS19' 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 MMS19 (gene ID: MMS19, UniProt: Q96T76) 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.

Plan
Objective 1 (verification). MMS19 is the correct human target: UniProt Q96T76 encodes the human homolog of yeast Met18/Mms19, also known as hMMS19/MMS19L, belonging to the MET18/MMS19 family with HEAT/ARM-like repeats. Organism: Homo sapiens. This aligns with the literature that consistently refers to MMS19 as the largest subunit of the CIA targeting complex and the human homolog of yeast Met18 (Met18/Mms19) with alpha-solenoid/HEAT-repeat architecture (see recent reviews) (frigerio2025controlofreplication pages 10-12, petronek2023maintenanceofgenome pages 1-2).

Objective 2. Key concepts and definitions (current understanding)
- Cytosolic iron–sulfur assembly (CIA) machinery and targeting complex: The CIA pathway completes the maturation of [4Fe–4S] clusters and delivers them to cytosolic and nuclear client proteins. A late-acting CIA β€œtargeting complex” (CTC) composed of MMS19, CIAO1 (Cia1), and CIA2B/FAM96B (Cia2) recognizes specific client proteins and mediates Fe–S cluster insertion, linking Fe–S biogenesis to DNA metabolism and genome integrity (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398, Mar 2023) (petronek2023maintenanceofgenome pages 1-2, petronek2023maintenanceofgenome pages 2-3).
- Fe–S client proteins: Enzymes that require insertion of an Fe–S cofactor for stability or activity. Many core DNA replication/repair enzymes (polymerases, primase, helicases) are Fe–S clients; their maturation depends on the CIA targeting complex (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 8-9).

Objective 3. Molecular function of MMS19 and its partners
- MMS19 serves as the central scaffold/bridging component of the CIA targeting complex, forming a ternary complex with CIAO1 and CIA2B/FAM96B. MMS19’s C-terminus interfaces with CIA2B; CIA2B bridges MMS19 to CIAO1, establishing the client-binding and delivery platform. MMS19 also stabilizes CIA2B and contributes additional client interaction surfaces beyond the high-affinity site on CIAO1 (Cells, 2025; https://doi.org/10.3390/cells14060442, Mar 2025; Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13, petronek2023maintenanceofgenome pages 2-3).
- Upstream/associated CIA factors: IOP1/NARFL (CIAO3) participates as an external component in the MMS19-dependent pathway, interfacing between the late-acting assembly module and the targeting complex that receives the mature [4Fe–4S] cluster (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 9-9, petronek2023maintenanceofgenome pages 2-3).

Objective 4. Validated client proteins of the MMS19/CTC pathway
- Helicases: XPD/ERCC2 (a TFIIH component essential for transcription/NER) and FANCJ/BRIP1 are established Fe–S clients whose maturation depends on MMS19. Structural and functional work on XPD defined its Fe–S domain; MMS19-dependent targeting is required for assembly into TFIIH. FANCJ/BRIP1 Fe–S coordination underpins G4 resolution and ICL repair (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398; Nucleic Acids Research, 2024; https://doi.org/10.1093/nar/gkae617, Jul 2024) (petronek2023maintenanceofgenome pages 9-9, petronek2023maintenanceofgenome pages 3-4, li2024thecriticalrole pages 9-9).
- DNA replication machinery: Catalytic subunits of DNA polymerases (Pol Ξ΄/POLD1, Pol Ξ΅/POLE1, Pol Ξ± complex), primase (PRIM2 [4Fe–4S] redox switch), and the helicase/nuclease DNA2 rely on Fe–S cofactors and are noted as clients regulated by the CIA targeting complex (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 8-9).
- Additional DNA repair helicases/enzymes: RTEL1, DDX11 (ChlR1), MUTYH, and NTHL1 are listed as Fe–S enzymes whose maturation is linked to the CIA targeting module (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 3-4).

Objective 5. Biological processes and pathways
- Transcription and NER via TFIIH: The XPD/ERCC2 Fe–S domain is inserted by the CIA targeting complex in the cytoplasm prior to nuclear import and TFIIH assembly. MMS19 depletion compromises XPD levels and TFIIH function, impacting nucleotide excision repair and transcription initiation (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 8-9, petronek2023maintenanceofgenome pages 3-4).
- DNA replication and replication stress response: MMS19 supports maturation of primase, polymerases, and helicases necessary for DNA synthesis and fork stability. Loss of MMS19/CIA2B increases sensitivity to replication stress (e.g., hydroxyurea) and perturbs checkpoint signaling; some cancer cells (e.g., TNBC) become more sensitive to ATR/CHK1 inhibitors when MMS19/CIA2B are depleted, highlighting therapeutic interactions with replication stress pathways (Cells, 2025; https://doi.org/10.3390/cells14060442) (frigerio2025controlofreplication pages 12-13).
- Genome stability and chromosome segregation: MMS19 deficiency impairs maturation/stability of multiple genome maintenance enzymes, causing sensitivity to genotoxic agents (e.g., UV, MMS), defects in chromosome segregation, and broader genome instability phenotypes (Cells, 2025; https://doi.org/10.3390/cells14060442; Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (frigerio2025controlofreplication pages 10-12, petronek2023maintenanceofgenome pages 9-9, petronek2023maintenanceofgenome pages 1-2).

Objective 6. Subcellular localization and trafficking
- MMS19 acts predominantly as a cytosolic factor in the CIA targeting complex. Client Fe–S insertion occurs in the cytoplasm prior to nuclear import, as shown for XPD/ERCC2 before TFIIH assembly. Thus, MMS19 executes its primary role in the cytosol while enabling nuclear client maturation for functions in replication, repair, and transcription (Frontiers in Genetics, 2023; https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 1-2).

Objective 7. Structural/domain insights
- Architecture: MMS19 is an approximately 118 kDa alpha-solenoid composed of HEAT repeats (ARM/HEAT-like fold). The C-terminal region binds CIA2B; lysines in specific helices can regulate CIA2B interaction. MMS19 displays conformational plasticity to accommodate different client shapes (e.g., globular DNA2 vs elongated primase), suggesting dynamic remodeling during client engagement and Fe–S transfer (Cells, 2025; https://doi.org/10.3390/cells14060442) (frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13).
- Oligomerization (conserved insight from yeast Met18): Yeast Met18 (MMS19 homolog) can form tetramers/hexamers that disassemble upon Cia2 binding, exposing client/Cia2 interaction surfacesβ€”supporting a model where MMS19’s flexibility and assembly state regulate client recruitment in the targeting complex (Cells, 2025; https://doi.org/10.3390/cells14060442) (frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13).

Objective 8. Disease links, clinical relevance, and applications
- Human genetic disease: Defects in the CIA targeting axis (CIAO1 and MMS19) cause severe neuromuscular/neurodegenerative disorders, underscoring the essential role of nucleocytoplasmic Fe–S protein maturation in human tissues (medRxiv 2023 preprint https://doi.org/10.1101/2023.12.20.23300170; Genetics in Medicine 2024; https://doi.org/10.1016/j.gim.2024.101104, Jun 2024) (li2024thecriticalrole pages 9-9).
- Cancer relevance and therapeutics: MMS19/CTC supports replication stress tolerance. Depletion of MMS19 or CIA2B sensitizes certain cancer cells (e.g., triple-negative breast cancer) to ATR/CHK1 pathway inhibitors, suggesting synthetic vulnerabilities that could be exploited therapeutically (Cells, 2025; https://doi.org/10.3390/cells14060442) (frigerio2025controlofreplication pages 12-13).

Objective 9. Recent developments (prioritized 2023–2024) with data/statistics where available
- 2023–2024 authoritative review of the late-acting CIA pathway and genome integrity: Petronek & Allen (Frontiers in Genetics, Mar 2023) consolidates evidence that MMS19 is the central scaffold of the CIA targeting complex, lists numerous DNA metabolic Fe–S clients (polymerases, primase, helicases) and emphasizes cytosolic insertion prior to nuclear function; includes discussion of reduced POLD1, FANCJ, and XPD expression upon MMS19 depletion (https://doi.org/10.3389/fgene.2023.1152398) (petronek2023maintenanceofgenome pages 9-9, petronek2023maintenanceofgenome pages 8-9, petronek2023maintenanceofgenome pages 2-3, petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 1-2).
- 2024 primary study (model organism) advancing CTC biology: Li et al. demonstrate that loss of mms-19 in C. elegans mislocalizes FANCJ/BRIP1 ortholog (DOG-1), increases DNA damage sensitivity, and genetically distinguishes essential roles of CIAO1/CIAO2B from nonessential mms-19 in worm development, highlighting conserved roles of MMS19/CTC in helicase stability and nuclear localization (Nucleic Acids Research, Jul 2024; https://doi.org/10.1093/nar/gkae617) (li2024thecriticalrole pages 9-9).
- 2023–2025 mechanistic synthesis: Frigerio et al. review the CIA machinery in replication stress, compiling structural/functional insights into MMS19’s HEAT-repeat architecture, client-binding interfaces, conformational plasticity, and therapeutic implications of MMS19/CIA2B depletion for ATR/CHK1 inhibitor sensitivity (Cells, Mar 2025; https://doi.org/10.3390/cells14060442). Although 2025, it directly synthesizes 2023–2024 primary findings (frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13).

Objective 10. Expert interpretation and analysis
- Primary function: MMS19 is a non-enzymatic scaffold/adaptor in the CIA targeting complex, required for the selective recognition and delivery of mature [4Fe–4S] clusters to diverse nucleocytoplasmic client proteins. It confers substrate specificity and stabilizes the targeting platform via interactions with CIAO1 and CIA2B. By enabling Fe–S insertion into clients such as XPD, FANCJ, primase, DNA2, and replicative polymerases, MMS19 indirectly supports transcription (TFIIH/NER), DNA replication, and repair, thereby preserving genome stability. The strongest mechanistic evidence places Fe–S insertion in the cytosol before nuclear complex assembly (e.g., TFIIH), consistent with a cytosolic site of action for MMS19 (Frontiers in Genetics, 2023; Cells, 2025) (petronek2023maintenanceofgenome pages 3-4, frigerio2025controlofreplication pages 10-12, petronek2023maintenanceofgenome pages 2-3).
- Localization and dynamics: The cytosolic targeting complex engages clients via multi-site binding (CIAO1 high-affinity site plus MMS19 N-terminal surface), and likely undergoes client-induced conformational rearrangements to coordinate Fe–S delivery. Yeast homolog studies suggest oligomerization states are regulated by Cia2 binding, which may be conserved in humans (Cells, 2025) (frigerio2025controlofreplication pages 12-13, frigerio2025controlofreplication pages 10-12).
- Disease and applications: Given the breadth of Fe–S clients in DNA metabolism, partial defects in MMS19/CTC may produce pleiotropic genome instability, while complete defects in upstream factors (e.g., CIAO1) cause severe multisystem disease. In oncology, targeting replication stress pathways in the context of weakened CIA targeting (e.g., MMS19 or CIA2B hypofunction) may produce therapeutic synergies with ATR/CHK1 inhibitors (Cells, 2025; Frontiers in Genetics, 2023) (frigerio2025controlofreplication pages 12-13, petronek2023maintenanceofgenome pages 9-9).

Objective 11. References with URLs and dates (selected, recent and authoritative)
- Petronek MS, Allen BG. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (CIA) complex. Frontiers in Genetics. Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398 (petronek2023maintenanceofgenome pages 1-2, petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 2-3, petronek2023maintenanceofgenome pages 8-9, petronek2023maintenanceofgenome pages 9-9).
- Li X et al. The critical role of the iron–sulfur cluster and CTC components in DOG-1/BRIP1 function in Caenorhabditis elegans. Nucleic Acids Research. Jul 2024. URL: https://doi.org/10.1093/nar/gkae617 (li2024thecriticalrole pages 9-9).
- Frigerio C et al. Control of replication stress response by cytosolic Fe-S cluster assembly (CIA) machinery. Cells. Mar 2025. URL: https://doi.org/10.3390/cells14060442 (frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13).

Conclusion
Human MMS19 (UniProt Q96T76) is a HEAT/ARM-like, alpha-solenoid scaffold of the CIA targeting complex that partners with CIAO1 and CIA2B/FAM96B to recruit and mature diverse Fe–S client proteins. Through cytosolic Fe–S insertion into key nucleic acid enzymesβ€”most notably XPD/ERCC2 (TFIIH), FANCJ/BRIP1, primase, DNA polymerases, DNA2, and othersβ€”MMS19 supports transcription-coupled NER, DNA replication, and replication stress responses, safeguarding chromosome segregation and genome stability. Recent work (2023–2024) consolidates MMS19’s central role in nucleocytoplasmic Fe–S delivery and links disruption of the CIA targeting axis to human neurogenetic disease and emerging therapeutic strategies leveraging replication stress vulnerabilities (URLs above) (petronek2023maintenanceofgenome pages 1-2, petronek2023maintenanceofgenome pages 3-4, petronek2023maintenanceofgenome pages 2-3, petronek2023maintenanceofgenome pages 8-9, petronek2023maintenanceofgenome pages 9-9, li2024thecriticalrole pages 9-9, frigerio2025controlofreplication pages 10-12, frigerio2025controlofreplication pages 12-13).

References

  1. (frigerio2025controlofreplication pages 10-12): Chiara Frigerio, Michela Galli, Sara Castelli, Aurora Da Prada, and Michela Clerici. Control of replication stress response by cytosolic fe-s cluster assembly (cia) machinery. Cells, 14:442, Mar 2025. URL: https://doi.org/10.3390/cells14060442, doi:10.3390/cells14060442. This article has 3 citations and is from a poor quality or predatory journal.

  2. (petronek2023maintenanceofgenome pages 1-2): M. S. Petronek and B. G. Allen. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (cia) complex. Frontiers in Genetics, Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398, doi:10.3389/fgene.2023.1152398. This article has 15 citations and is from a peer-reviewed journal.

  3. (petronek2023maintenanceofgenome pages 2-3): M. S. Petronek and B. G. Allen. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (cia) complex. Frontiers in Genetics, Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398, doi:10.3389/fgene.2023.1152398. This article has 15 citations and is from a peer-reviewed journal.

  4. (petronek2023maintenanceofgenome pages 3-4): M. S. Petronek and B. G. Allen. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (cia) complex. Frontiers in Genetics, Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398, doi:10.3389/fgene.2023.1152398. This article has 15 citations and is from a peer-reviewed journal.

  5. (petronek2023maintenanceofgenome pages 8-9): M. S. Petronek and B. G. Allen. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (cia) complex. Frontiers in Genetics, Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398, doi:10.3389/fgene.2023.1152398. This article has 15 citations and is from a peer-reviewed journal.

  6. (frigerio2025controlofreplication pages 12-13): Chiara Frigerio, Michela Galli, Sara Castelli, Aurora Da Prada, and Michela Clerici. Control of replication stress response by cytosolic fe-s cluster assembly (cia) machinery. Cells, 14:442, Mar 2025. URL: https://doi.org/10.3390/cells14060442, doi:10.3390/cells14060442. This article has 3 citations and is from a poor quality or predatory journal.

  7. (petronek2023maintenanceofgenome pages 9-9): M. S. Petronek and B. G. Allen. Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (cia) complex. Frontiers in Genetics, Mar 2023. URL: https://doi.org/10.3389/fgene.2023.1152398, doi:10.3389/fgene.2023.1152398. This article has 15 citations and is from a peer-reviewed journal.

  8. (li2024thecriticalrole pages 9-9): Xiao Li, Ivette Maria Menendez Perdomo, Victoria Rodrigues Alves Barbosa, Catherine Diao, and Maja Tarailo-Graovac. The critical role of the iron–sulfur cluster and ctc components in dog-1/brip1 function in caenorhabditis elegans. Nucleic Acids Research, 52:9586-9595, Jul 2024. URL: https://doi.org/10.1093/nar/gkae617, doi:10.1093/nar/gkae617. This article has 1 citations and is from a highest quality peer-reviewed journal.

Citations

  1. petronek2023maintenanceofgenome pages 3-4
  2. frigerio2025controlofreplication pages 12-13
  3. li2024thecriticalrole pages 9-9
  4. frigerio2025controlofreplication pages 10-12
  5. petronek2023maintenanceofgenome pages 1-2
  6. petronek2023maintenanceofgenome pages 2-3
  7. petronek2023maintenanceofgenome pages 8-9
  8. petronek2023maintenanceofgenome pages 9-9
  9. 4Fe–4S
  10. https://doi.org/10.3389/fgene.2023.1152398,
  11. https://doi.org/10.3389/fgene.2023.1152398
  12. https://doi.org/10.3390/cells14060442,
  13. https://doi.org/10.3389/fgene.2023.1152398;
  14. https://doi.org/10.1093/nar/gkae617,
  15. https://doi.org/10.3390/cells14060442
  16. https://doi.org/10.3390/cells14060442;
  17. https://doi.org/10.1101/2023.12.20.23300170;
  18. https://doi.org/10.1016/j.gim.2024.101104,
  19. https://doi.org/10.1093/nar/gkae617

πŸ“„ View Raw YAML

 
id: Q96T76
gene_symbol: MMS19
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:22678361
      supporting_text: we demonstrate that MMS19 forms a complex with the 
        cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18
    - reference_id: PMID:22678362
      supporting_text: MMS19 functions as part of the CIA targeting complex that
        specifically interacts with and facilitates iron-sulfur cluster 
        insertion into apoproteins
    - reference_id: PMID:23585563
      supporting_text: Here, we show that MMS19, MIP18, and CIAO1 form a tight 
        "core" complex and that IOP1 is an "external" component of this complex
    - reference_id: file:human/MMS19/MMS19-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: 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
- term:
    id: GO:0071817
    label: MMXD complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: 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
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Nuclear localization of MMS19 is inferred from UniProt subcellular 
      location annotation. This is supported by IDA evidence from PMID:20797633.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMS19, MIP18, and XPD localized to the mitotic spindle 
        during mitosis
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Centrosome localization is inferred from UniProt. MMS19 localizes 
      to centrosomes during mitosis, particularly during prophase.
    action: ACCEPT
    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.
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Spindle localization is inferred from UniProt and supported by 
      direct experimental evidence showing MMS19 localizes to mitotic spindles.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMS19, MIP18, and XPD localized to the mitotic spindle 
        during mitosis
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: 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
    - reference_id: PMID:22678361
      supporting_text: In the absence of MMS19, a failure to transfer Fe-S 
        clusters to target proteins is associated with Fe-S protein instability
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: MMS19 indirectly supports transcription by maturing XPD, an Fe-S 
      helicase that is a component of the TFIIH general transcription factor.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: 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
    - reference_id: PMID:11071939
      supporting_text: Co-immunoprecipitation experiments revealed that hMMS19 
        directly interacts with the XPB and XPD subunits of NER-transcription 
        factor TFIIH
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: MMS19 supports DNA damage response indirectly by maturing Fe-S 
      proteins involved in DNA damage sensing and repair.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: The function of MMS19 in the maturation of crucial 
        components of DNA metabolism may explain the sensitivity of MMS19 
        mutants to DNA damage
- term:
    id: GO:0007059
    label: chromosome segregation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: MMS19 participates in chromosome segregation through the MMXD 
      complex. Knockdown of MMS19 causes improper chromosome segregation.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: The siRNA-mediated knockdown of MMS19, MIP18, or XPD led 
        to improper chromosome segregation and the accumulation of nuclei with 
        abnormal shapes
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: This annotation is logically inferred from the transcription 
      coactivator activity annotation. MMS19 can act as a coactivator for 
      estrogen receptor-mediated transcription.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: In contrast, over expression of the full-length hMMS19 
        enhances ER-mediated transcriptional activation
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Protein maturation role inferred from InterPro MMS19 domain 
      annotation. This is correct but general - MMS19 specifically matures Fe-S 
      proteins.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17314511
  review:
    summary: Protein binding to c-MYC detected in high-throughput TAP/MudPIT 
      screen. The biological significance is unclear.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17314511
      supporting_text: Large-scale identification of c-MYC-associated proteins 
        using a combined TAP/MudPIT approach.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: Protein binding to CIAO1 detected by mass spectrometry. This 
      interaction is functionally relevant as CIAO1 is a core CIA targeting 
      complex component.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0097361
      label: cytosolic [4Fe-4S] assembly targeting complex
    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions
        by mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  review:
    summary: Protein binding to CIAO1 from next-generation sequencing 
      interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Duplicative with other CIAO1 interaction annotations. The generic 
      "protein binding" term is uninformative when the specific functional 
      complex (CIA targeting complex) is known.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome 
        datasets.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23585563
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0097361
      label: cytosolic [4Fe-4S] assembly targeting complex
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: 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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  review:
    summary: Protein binding to CIAO1 from chromatin-related protein interaction
      study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Duplicative with other CIAO1 interaction annotations. The CIAO1 
      interaction is well established through other studies and the generic 
      "protein binding" is uninformative.
    supported_by:
    - reference_id: PMID:24981860
      supporting_text: 2014 Jun 26. Human-chromatin-related protein interactions
        identify a demethylase complex required for chromosome segregation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28178521
  review:
    summary: Protein binding to CIAO1, XPD/ERCC2, RTEL1, and CIAO2B from a study
      characterizing the CIA targeting complex client binding sites.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0097361
      label: cytosolic [4Fe-4S] assembly targeting complex
    supported_by:
    - reference_id: PMID:28178521
      supporting_text: The CIA Targeting Complex Is Highly Regulated and 
        Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: Protein binding to CIAO1 and CIAO2B from human interactome 
      architecture study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Large-scale interactome study. These interactions are established 
      but "protein binding" is uninformative when the functional complex (CIA 
      targeting complex) is known.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein 
        communities and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Protein binding to CIAO1 and CIAO2B from dual proteome-scale 
      interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput study confirming known interactions. The generic 
      "protein binding" term adds no functional insight beyond what is captured 
      by CIA complex annotations.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
        cell-specific remodeling of the human interactome.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: CIA targeting complex membership inferred by combined automated 
      annotation methods.
    action: ACCEPT
    reason: This is correct and supported by experimental evidence. Duplicative 
      with IDA and IBA annotations but provides additional computational 
      support.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nucleoplasm localization determined by HPA immunofluorescence data 
      curation.
    action: ACCEPT
    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.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IMP
  original_reference_id: PMID:22678361
  review:
    summary: Protein maturation function demonstrated by mutant phenotype - 
      MMS19 knockdown leads to instability of Fe-S client proteins.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:22678361
      supporting_text: In the absence of MMS19, a failure to transfer Fe-S 
        clusters to target proteins is associated with Fe-S protein instability
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IDA
  original_reference_id: PMID:29225034
  review:
    summary: Protein maturation function demonstrated by direct assay - study 
      showed MMS19 is required for Fe-S cluster incorporation into DNA repair 
      enzymes.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:29225034
      supporting_text: Overexpression or knockout of MAGE-F1 altered Fe-S 
        incorporation into MMS19-dependent DNA repair enzymes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:23585563
  review:
    summary: Cytoplasmic localization from ComplexPortal annotation based on 
      PMID:23585563.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Here, we show that MMS19, MIP18, and CIAO1 form a tight 
        "core" complex and that IOP1 is an "external" component of this complex
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: NAS
  original_reference_id: PMID:23585563
  review:
    summary: Iron-sulfur cluster assembly process annotation from ComplexPortal.
      MMS19 functions in the late stages of cytosolic Fe-S protein assembly.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Recent studies have revealed that MMS19 and cytosolic 
        iron-sulfur cluster assembly (CIA) factors form a complex and have 
        central roles in CIA pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30742009
  review:
    summary: Protein binding to CIAO2B. The study found CCDC117 interacts with 
      MMS19 indirectly through the CIA complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: The CIAO2B interaction is established but "protein binding" is 
      uninformative. The functional complex (CIA targeting complex) is already 
      annotated.
    supported_by:
    - reference_id: PMID:30742009
      supporting_text: Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates 
        DNA Metabolism and Proliferation.
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:23585563
  review:
    summary: CIA targeting complex membership demonstrated by 
      co-immunoprecipitation and biochemical characterization showing MMS19 
      forms core complex with CIAO1, MIP18, and external component IOP1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Here, we show that MMS19, MIP18, and CIAO1 form a tight 
        "core" complex and that IOP1 is an "external" component of this complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23891004
  review:
    summary: Protein binding to CIAO1 and CIAO2B from study characterizing CIA2A
      and CIA2B functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Valid interactions but "protein binding" is uninformative. The 
      functional complex annotation (GO:0097361) provides better context.
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: 2013 Jul 25. Human CIA2A-FAM96A and CIA2B-FAM96B 
        integrate iron homeostasis and maturation of different subsets of 
        cytosolic-nuclear iron-sulfur proteins.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: Membrane localization from high-throughput direct assay (NK cell 
      membrane proteome study).
    action: UNDECIDED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Defining the membrane proteome of NK cells.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22678361
  review:
    summary: Cytoplasmic localization directly demonstrated by Gari et al. 2012.
    action: ACCEPT
    reason: The cytoplasm is where MMS19 executes its primary function of Fe-S 
      cluster delivery to client proteins. This is well-established experimental
      evidence.
    supported_by:
    - reference_id: PMID:22678361
      supporting_text: Cytoplasmic MMS19 also binds to multiple nuclear Fe-S 
        proteins involved in DNA metabolism
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:22678361
  review:
    summary: CIA targeting complex membership demonstrated by 
      co-immunoprecipitation showing MMS19 forms complex with CIA proteins 
      CIAO1, IOP1, and MIP18.
    action: ACCEPT
    reason: This is primary experimental evidence establishing MMS19 as a CIA 
      targeting complex component.
    supported_by:
    - reference_id: PMID:22678361
      supporting_text: we demonstrate that MMS19 forms a complex with the 
        cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:22678362
  review:
    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.
    action: ACCEPT
    reason: This landmark study identified MMS19 as part of the CIA targeting 
      complex that facilitates Fe-S cluster insertion into DNA metabolism 
      proteins.
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: we identify MMS19 as a member of the cytosolic 
        iron-sulfur protein assembly (CIA) machinery. MMS19 functions as part of
        the CIA targeting complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20797633
  review:
    summary: Protein binding to CIAO2B from the MMXD complex study.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0071817
      label: MMXD complex
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMXD, a TFIIH-independent XPD-MMS19 protein complex 
        involved in chromosome segregation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:20797633
  review:
    summary: Nuclear localization demonstrated by immunofluorescence in the MMXD
      complex study.
    action: ACCEPT
    reason: Nuclear localization is experimentally validated and consistent with
      MMS19's role in the MMXD complex and maturation of nuclear Fe-S proteins.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMS19, MIP18, and XPD localized to the mitotic spindle 
        during mitosis
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20797633
  review:
    summary: Cytoplasmic localization demonstrated in the MMXD complex study.
    action: ACCEPT
    reason: Cytoplasm is the primary site of MMS19 function. Experimental 
      validation from multiple independent studies.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMXD, a TFIIH-independent XPD-MMS19 protein complex 
        involved in chromosome segregation.
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IDA
  original_reference_id: PMID:20797633
  review:
    summary: Spindle localization directly demonstrated by immunofluorescence 
      during mitosis.
    action: ACCEPT
    reason: MMS19 localizes to the mitotic spindle as part of the MMXD complex. 
      This is required for its role in chromosome segregation.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMS19, MIP18, and XPD localized to the mitotic spindle 
        during mitosis
- term:
    id: GO:0071817
    label: MMXD complex
  evidence_type: IDA
  original_reference_id: PMID:20797633
  review:
    summary: MMXD complex membership directly demonstrated. MMS19 was identified
      as a core component of this TFIIH-independent XPD-containing complex.
    action: ACCEPT
    reason: This study discovered and characterized the MMXD complex, showing 
      MMS19 is an essential component required for chromosome segregation.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: the MMS19-XPD protein complex, now designated MMXD 
        (MMS19-MIP18-XPD), is required for proper chromosome segregation
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:11279242
  review:
    summary: Transcription coactivator activity demonstrated by mutant phenotype
      - overexpression of hMMS19 enhanced ER-mediated transcription while 
      dominant negative construct inhibited it.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: In contrast, over expression of the full-length hMMS19 
        enhances ER-mediated transcriptional activation
- term:
    id: GO:0005675
    label: transcription factor TFIIH holo complex
  evidence_type: NAS
  original_reference_id: PMID:11279242
  review:
    summary: TFIIH complex association inferred from interaction with XPD and 
      XPB, which are TFIIH components.
    action: REMOVE
    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.
    additional_reference_ids:
    - PMID:22678361
    - PMID:22678362
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: 2001 Mar 28. The human homologue of the yeast DNA repair 
        and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen 
        receptor.
    - reference_id: PMID:22678361
      supporting_text: Jun 7. MMS19 links cytoplasmic iron-sulfur cluster 
        assembly to DNA metabolism.
    - reference_id: PMID:22678362
      supporting_text: Jun 7. MMS19 assembles iron-sulfur proteins required for 
        DNA metabolism and genomic integrity.
- term:
    id: GO:0030159
    label: signaling receptor complex adaptor activity
  evidence_type: NAS
  original_reference_id: PMID:11279242
  review:
    summary: Signaling receptor complex adaptor activity inferred from the 
      estrogen receptor coactivator study.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: 2001 Mar 28. The human homologue of the yeast DNA repair 
        and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen 
        receptor.
- term:
    id: GO:0030331
    label: nuclear estrogen receptor binding
  evidence_type: IPI
  original_reference_id: PMID:11279242
  review:
    summary: Estrogen receptor binding demonstrated by co-immunoprecipitation. 
      MMS19 interacted with ER in ligand-independent manner.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: the human MMS19 also interacts with estrogen receptors in
        a ligand-independent manner
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: NAS
  original_reference_id: PMID:11279242
  review:
    summary: Adaptor activity inferred from the ER coactivator study, suggesting
      MMS19 bridges ER and TFIIH.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0097361
      label: cytosolic [4Fe-4S] assembly targeting complex
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: MMS19 thus serves as an adapter between early-acting CIA 
        components and a subset of cellular iron-sulfur proteins
    - reference_id: PMID:11279242
      supporting_text: 2001 Mar 28. The human homologue of the yeast DNA repair 
        and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen 
        receptor.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11279242
  review:
    summary: Protein binding to RAC3/NCOA3 demonstrated in the ER coactivator 
      study.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:11279242
      supporting_text: 2001 Mar 28. The human homologue of the yeast DNA repair 
        and TFIIH regulator MMS19 is an AF-1-specific coactivator of estrogen 
        receptor.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:11071939
  review:
    summary: Nuclear localization from early characterization study. "Traceable 
      Author Statement" evidence from the paper that cloned human MMS19.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11071939
      supporting_text: The expression profile and nuclear location are 
        consistent with a repair function
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: The siRNA-mediated knockdown of MMS19, MIP18, or XPD led 
        to improper chromosome segregation and the accumulation of nuclei with 
        abnormal shapes
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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping
  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:0000108
  title: Automatic assignment of GO terms using logical inference, based on 
    inter-ontology links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11071939
  title: Cloning of a human homolog of the yeast nucleotide excision repair gene
    MMS19 and interaction with transcription repair factor TFIIH via the XPB and
    XPD helicases.
  findings:
  - statement: First cloning of human MMS19, showing interaction with XPB and 
      XPD subunits of TFIIH
  - statement: Established nuclear localization and ubiquitous expression
- id: PMID:11279242
  title: The human homologue of the yeast DNA repair and TFIIH regulator MMS19 
    is an AF-1-specific coactivator of estrogen receptor.
  findings:
  - statement: MMS19 interacts with RAC3/NCOA3 and estrogen receptor
  - statement: Acts as AF-1-specific coactivator enhancing ER-mediated 
      transcription
  - statement: Early interpretation as transcription adapter (superseded by Fe-S
      cluster delivery model)
- id: PMID:17314511
  title: Large-scale identification of c-MYC-associated proteins using a 
    combined TAP/MudPIT approach.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass 
    spectrometry.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20797633
  title: MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in 
    chromosome segregation.
  findings:
  - statement: Discovery of MMXD complex containing MMS19, MIP18, XPD, CIAO1, 
      and ANT2
  - statement: MMXD localizes to mitotic spindle during mitosis
  - statement: MMS19 knockdown causes improper chromosome segregation
  - statement: MMXD is distinct from TFIIH
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:22678361
  title: MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.
  findings:
  - statement: MMS19 forms complex with CIA proteins CIAO1, IOP1, and MIP18
  - statement: Cytoplasmic MMS19 binds multiple nuclear Fe-S proteins involved 
      in DNA metabolism
  - statement: MMS19 functions as platform for Fe-S cluster transfer to DNA 
      repair proteins
  - statement: MMS19 knockout mice die during preimplantation
- id: PMID:22678362
  title: MMS19 assembles iron-sulfur proteins required for DNA metabolism and 
    genomic integrity.
  findings:
  - statement: MMS19 identified as member of CIA machinery
  - statement: Functions as adapter between early-acting CIA components and Fe-S
      client proteins
  - statement: Client proteins include those for DNA replication, repair, and 
      telomere maintenance
  - statement: Explains sensitivity of MMS19 mutants to DNA damage
- id: PMID:23585563
  title: IOP1 protein is an external component of the human cytosolic 
    iron-sulfur cluster assembly (CIA) machinery.
  findings:
  - statement: MMS19, MIP18, and CIAO1 form tight core complex
  - statement: IOP1 is external component
  - statement: MMS19 interacts directly with target proteins
  - statement: MIP18 bridges MMS19 and CIAO1
- id: PMID:23891004
  title: Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and 
    maturation of different subsets of cytosolic-nuclear iron-sulfur proteins.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase 
    complex required for chromosome segregation.
  findings: []
- id: PMID:28178521
  title: The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct
    Binding Sites for Client Iron-Sulfur Proteins.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and 
    disease networks.
  findings: []
- id: PMID:29225034
  title: Cytosolic Iron-Sulfur Assembly Is Evolutionarily Tuned by a 
    Cancer-Amplified Ubiquitin Ligase.
  findings:
  - statement: MAGE-F1-NSE1 E3 ligase regulates CIA pathway through MMS19 
      ubiquitination
  - statement: MMS19 degradation affects Fe-S incorporation into DNA repair 
      enzymes
  - statement: MAGE-F1 amplification in cancer increases mutational burden
- id: PMID:30742009
  title: Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism 
    and Proliferation.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome.
  findings: []
- id: file:human/MMS19/MMS19-deep-research-falcon.md
  title: Deep research report on MMS19
  findings: []
core_functions:
- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  description: MMS19 is the central scaffold component of the CIA targeting 
    complex, functioning as an adaptor between early-acting CIA components and 
    Fe-S client proteins. MMS19's HEAT-repeat architecture provides the binding 
    platform for both complex partners (CIAO1, CIAO2B, CIAO3) and client Fe-S 
    proteins (XPD, FANCJ, RTEL1, polymerases). Multiple studies using co-IP and 
    mass spectrometry have demonstrated this complex formation (PMID:22678361, 
    PMID:22678362, PMID:23585563).
  directly_involved_in:
  - id: GO:0016226
    label: iron-sulfur cluster assembly
  - id: GO:0051604
    label: protein maturation
  locations:
  - id: GO:0005737
    label: cytoplasm
  in_complex:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  supported_by:
  - reference_id: PMID:22678362
    supporting_text: MMS19 thus serves as an adapter between early-acting CIA 
      components and a subset of cellular iron-sulfur proteins
  - reference_id: PMID:23585563
    supporting_text: MMS19, MIP18, and CIAO1 form a tight 'core' complex
- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  description: MMS19 participates in chromosome segregation through the MMXD 
    complex (MMS19-MIP18-XPD). This complex localizes to the mitotic spindle and
    is required for proper chromosome segregation. MMS19 knockdown causes 
    improper chromosome segregation and abnormal nuclear morphology.
  directly_involved_in:
  - id: GO:0007059
    label: chromosome segregation
  locations:
  - id: GO:0005819
    label: spindle
  - id: GO:0005813
    label: centrosome
  in_complex:
    id: GO:0071817
    label: MMXD complex
  supported_by:
  - reference_id: PMID:20797633
    supporting_text: The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to
      improper chromosome segregation and the accumulation of nuclei with 
      abnormal shapes
proposed_new_terms: []
suggested_questions:
- question: How does MMS19 recognize and select specific Fe-S client proteins 
    from the proteome?
- question: What is the structural basis for MMS19's interaction with different 
    client proteins?
- question: Is MMS19's role in chromosome segregation (via MMXD) entirely 
    dependent on XPD Fe-S cluster loading, or does it have additional functions?
suggested_experiments:
- description: Cryo-EM structure of MMS19 bound to different client proteins to 
    understand substrate recognition
- description: Proteomics to identify the complete set of MMS19-dependent Fe-S 
    client proteins in human cells
- description: Time-course experiments to determine the order of events in CIA 
    targeting complex assembly and client engagement
tags:
- iron-sulfur-cluster-biogenesis