CIAO1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016226 iron-sulfur cluster assembly	IBA GO_REF:0000033	ACCEPT	Summary: CIAO1 is a core component of the CIA targeting complex that mediates Fe-S cluster transfer to cytosolic and nuclear client proteins. The IBA annotation from phylogenetic inference is strongly supported by multiple human studies demonstrating CIAO1's essential role in Fe-S protein maturation (PMID:23891004, PMID:22678361, PMID:22678362, PMID:38950322). Reason: This annotation correctly captures CIAO1's central role in the CIA pathway. Multiple primary studies confirm CIAO1 functions in iron-sulfur cluster assembly by facilitating cluster transfer to cytosolic-nuclear Fe-S proteins (PMID:23891004). Loss of CIAO1 results in compromised biogenesis of Fe-S enzymes like POLD1 and DPYD (PMID:38950322). Supporting Evidence: PMID:23891004 CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19. The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins PMID:38950322 Functional assays revealed selective compromise of the biogenesis of Fe-S enzymes that are known clients of the CIA complex, namely dihydropyrimidine dehydrogenase (DPYD)
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IBA GO_REF:0000033	ACCEPT	Summary: CIAO1 is a core structural component of the cytosolic [4Fe-4S] assembly targeting complex (CTC), together with MMS19 and CIAO2B/FAM96B. The IBA annotation is well-supported by multiple experimental studies (PMID:22678361, PMID:22678362, PMID:23585563, PMID:23891004). Reason: This cellular component annotation accurately reflects CIAO1's established role as a core subunit of the CTC. Multiple independent studies have demonstrated this complex membership through co-immunoprecipitation and size exclusion chromatography. 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 PMID:23891004 CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: CIAO1 is a cytoplasmic protein that functions in the late-acting CIA machinery. This is supported by subcellular fractionation studies (PMID:23585563) and consistent with its role in cytosolic Fe-S protein assembly. Reason: The cytoplasmic localization is well-established experimentally and consistent with CIAO1's role in the cytosolic iron-sulfur protein assembly pathway. This IEA annotation is accurate. Supporting Evidence: PMID:38950322 the 3 core components of the CIA complex, which specifically localizes to the cytosolic compartment of mammalian cells file:human/CIAO1/CIAO1-deep-research-falcon.md CIAO1 is cytosolic and functions in the late cytosolic/nuclear Fe-S assembly step
GO:0007059 chromosome segregation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: CIAO1 is part of the MMXD complex (MMS19-MIP18-XPD) which localizes to the mitotic spindle during mitosis and is implicated in chromosome segregation (PMID:20797633). However, this appears to be a secondary role related to its function in maturing Fe-S proteins like XPD rather than a direct role in the segregation machinery. Reason: While CIAO1's involvement in chromosome segregation via the MMXD complex is documented (PMID:20797633), this is likely an indirect consequence of its role in maturing Fe-S cluster-containing proteins such as XPD that are required for proper chromosome segregation. The core function of CIAO1 is in Fe-S cluster assembly/transfer. Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis. The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to improper chromosome segregation
GO:0016226 iron-sulfur cluster assembly	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation based on automated methods correctly captures CIAO1's role in iron-sulfur cluster assembly, which is strongly supported by experimental evidence. Reason: This is a correct annotation that aligns with the experimentally verified function of CIAO1 in the CIA pathway. Supporting Evidence: PMID:23891004 CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly
GO:0071817 MMXD complex	IEA GO_REF:0000104	ACCEPT	Summary: CIAO1 was identified as a component of the MMXD complex (MMS19-MIP18-XPD-Ciao1-ANT2) by Ito et al. 2010 (PMID:20797633). This complex functions independently of TFIIH and is involved in chromosome segregation. Reason: This annotation is supported by direct experimental evidence from PMID:20797633 demonstrating CIAO1's membership in the MMXD complex. Supporting Evidence: PMID:20797633 the MMS19-XPD complex did not contain any other subunits of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and ANT2
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation correctly reflects CIAO1's membership in the cytosolic [4Fe-4S] assembly targeting complex, supported by extensive experimental data. Reason: Accurate annotation consistent with multiple experimental studies demonstrating CIAO1 is a core component of the CTC.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput protein interaction study. Protein binding is too general and uninformative for CIAO1's specific role as a scaffold/adapter in Fe-S cluster transfer. Reason: The term 'protein binding' is non-informative for CIAO1 which has a specific scaffold function in the CIA targeting complex. The actual molecular function involves acting as a client docking platform for Fe-S protein maturation, which is not well captured by this generic term. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: Large-scale mass spectrometry protein interaction mapping. Shows interaction with MMS19 (Q96T76) but 'protein binding' is too general. Reason: While the interaction data is valid, 'protein binding' does not capture the functional significance of CIAO1's role as a scaffold in 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: Next-generation sequencing interactome study showing interaction with MMS19 and CIAO2B (FAM96B). Generic protein binding annotation. Reason: The specific interactions are meaningful for understanding CIA complex assembly, but 'protein binding' is too vague to be informative. 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...	MARK AS OVER ANNOTATED	Summary: This publication (Seki et al. 2013) demonstrates specific interactions between CIAO1 and ERCC2/XPD, CIAO3/IOP1, and CIAO2B within the CIA complex. These are functionally relevant interactions for Fe-S cluster delivery. Reason: The underlying data is valuable but 'protein binding' is too generic. The interactions represent CIAO1's role as a scaffold in the CIA targeting complex. Supporting Evidence: PMID:23585563 MIP18 has a role to bridge MMS19 and CIAO1. CIAO1 also binds IOP1
GO:0005515 protein binding	IPI PMID:24245804 Viperin is an iron-sulfur protein that inhibits genome synth...	MARK AS OVER ANNOTATED	Summary: Shows interaction with viperin (RSAD2), an Fe-S protein that is a CIA client. Viperin requires Fe-S cluster for its antiviral activity. Reason: The interaction with viperin represents CIAO1's client interaction function, but 'protein binding' is uninformative. Supporting Evidence: PMID:24245804 Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity.
GO:0005515 protein binding	IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme...	MARK AS OVER ANNOTATED	Summary: Human chromatin-related protein interaction study showing interactions with MMS19, CIAO2A, and CIAO2B components of the CIA complex. Reason: Relevant interactions but generic protein binding term 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:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome study. Shows multiple interactions including with CIA complex components. Reason: High-throughput data; protein binding is too general for curation purposes. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:28178521 The CIA Targeting Complex Is Highly Regulated and Provides T...	MARK AS OVER ANNOTATED	Summary: This focused study on the CIA targeting complex demonstrates CIAO1 interactions with ERCC2/XPD and MMS19, providing important mechanistic insights into client binding by the CTC. Reason: Valuable mechanistic data about CIA targeting complex, but 'protein binding' is too generic. The publication supports the complex membership annotations. 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: Architecture of human interactome study showing interaction with MMS19. Reason: High-throughput interactome data; protein binding is uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	MARK AS OVER ANNOTATED	Summary: This study demonstrates formation of a stable ternary complex of CIAO3, CIAO1, and CIAO2A, with a [4Fe-4S] cluster. Important for understanding CIA machinery. Reason: Mechanistically important data, but 'protein binding' does not capture the specific scaffold function of CIAO1 in the CIA complex. Supporting Evidence: PMID:32222833 the formation of a stable, [4Fe-4S]-bound, complex, composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Reference map of human binary protein interactome showing multiple CIAO1 interactions. Reason: High-throughput interactome data; protein binding is too general. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale network study showing cell-specific CIAO1 interactions. Reason: Large-scale interaction data; protein binding is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study for structural and functional genomics. Reason: High-throughput data; protein binding is too general. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0051604 protein maturation	IGI PMID:17937914 Structure of the yeast WD40 domain protein Cia1, a component...	MODIFY	Summary: This study on yeast Cia1 structure demonstrates that human CIAO1 can functionally replace yeast Cia1 in supporting cytosolic Fe-S protein biogenesis. The protein maturation annotation refers to the maturation of Fe-S proteins through cluster insertion. Reason: While CIAO1 does participate in protein maturation (specifically of Fe-S proteins), a more precise annotation would be 'iron-sulfur cluster assembly' (GO:0016226) which is already present. The term 'protein maturation' is too general. Proposed replacements: iron-sulfur cluster assembly Supporting Evidence: PMID:17937914 We show that Ciao1 can functionally replace Cia1 and support cytosolic Fe/S protein biogenesis
GO:0051604 protein maturation	IMP PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas...	MODIFY	Summary: This study demonstrates that CIAO1 facilitates assembly/maturation of cytosolic-nuclear Fe-S proteins by participating in cluster insertion. While technically protein maturation, the more specific term 'iron-sulfur cluster assembly' better captures the function. Reason: The specific function is iron-sulfur cluster insertion into apo-proteins, which is already captured by GO:0016226. 'Protein maturation' is overly broad. Proposed replacements: iron-sulfur cluster assembly Supporting Evidence: PMID:23891004 The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IMP PMID:38950322 CIAO1 loss of function causes a neuromuscular disorder with ...	ACCEPT	Summary: This landmark 2024 study on CIAO1 loss-of-function patients demonstrates that CIAO1 is essential for CIA complex stability. Loss of CIAO1 leads to destabilization of MMS19 and FAM96B, confirming CIAO1's role as a core CTC component. Reason: Strong experimental evidence from patient-derived cells showing CIAO1 is essential for CTC stability and function. Supporting Evidence: PMID:38950322 CIAO1 protein levels were profoundly diminished in cytosolic lysates from P1-derived fibroblasts compared with parental cells (Figure 4, A and B, and Supplemental Figure 3, A and B), with a concomitant loss of the known CIAO1-interacting partners MMS19 and FAM96B (Figure 4A and Supplemental Figure 3, A and B)
GO:0005737 cytoplasm	NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Cytoplasmic localization stated in the context of CIA complex characterization. Reason: Consistent with experimental data showing CIAO1 functions in the cytosol as part of the CIA machinery. 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:0016226 iron-sulfur cluster assembly	NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: CIAO1's role in iron-sulfur cluster assembly is discussed in the context of the CIA pathway. Reason: Accurate annotation supported by the publication's characterization of the CIA complex and CIAO1's role in Fe-S protein maturation. 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:0005737 cytoplasm	NAS PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	ACCEPT	Summary: Cytoplasmic localization in context of CIA complex studies. Reason: Consistent with established cytosolic function of CIAO1. Supporting Evidence: PMID:32222833 Epub 2020 Mar 28. CIAO3 protein forms a stable ternary complex with two key players of the human cytosolic iron-sulfur cluster assembly machinery.
GO:0016226 iron-sulfur cluster assembly	IDA PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	ACCEPT	Summary: This study demonstrates CIAO1 forms a stable ternary complex with CIAO3 and CIAO2A that is [4Fe-4S]-bound, directly supporting its role in iron-sulfur cluster assembly. Reason: Direct experimental evidence showing CIAO1's participation in Fe-S cluster containing complexes. Supporting Evidence: PMID:32222833 the formation of a stable, [4Fe-4S]-bound, complex, composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
GO:0005737 cytoplasm	IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Direct experimental evidence for cytoplasmic localization from subcellular fractionation studies. Reason: IDA evidence directly demonstrates cytoplasmic localization of CIAO1. Supporting Evidence: PMID:38950322 the 3 core components of the CIA complex, which specifically localizes to the cytosolic compartment of mammalian cells 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:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Direct demonstration of CIAO1 as a core component of the CTC through co-immunoprecipitation and biochemical studies. Reason: Strong experimental evidence showing CIAO1 is a core CTC component. 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: This study demonstrates specific interactions between CIAO1 and multiple CIA components (CIAO2A, CIAO2B, MMS19) and client Fe-S proteins (ERCC2, POLD1, IREB2). Reason: The interactions are highly relevant for understanding CIA function, but 'protein binding' is too generic to be informative. The complex membership annotations better capture these functional relationships. Supporting Evidence: PMID:23891004 CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas...	ACCEPT	Summary: Comprehensive characterization of CIAO1 as a core component of the CTC, showing it forms distinct complexes with CIAO2A-CIAO1 and CIAO2B-CIAO1-MMS19. Reason: Key publication establishing CIAO1's role in the CIA targeting complex. Supporting Evidence: PMID:23891004 CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:22678361 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA ...	ACCEPT	Summary: This Science paper demonstrates MMS19 forms a complex with CIAO1 and other CIA factors (IOP1/CIAO3, MIP18/CIAO2B) that links cytoplasmic Fe-S assembly to DNA metabolism. Reason: Landmark study establishing the CIA targeting complex. Supporting Evidence: PMID:22678361 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: Companion Science paper demonstrating MMS19 as part of the CIA targeting complex that facilitates Fe-S cluster insertion into DNA metabolism proteins. Reason: Foundational study for understanding the CTC and CIAO1's role in it. 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
GO:0071817 MMXD complex	IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved...	ACCEPT	Summary: Direct identification of CIAO1 as a component of the MMXD complex (MMS19-MIP18-XPD-Ciao1-ANT2) through immunoprecipitation studies. Reason: Experimental evidence directly demonstrating CIAO1 is part of the MMXD complex. Supporting Evidence: PMID:20797633 the MMS19-XPD complex did not contain any other subunits of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and ANT2
GO:0006357 regulation of transcription by RNA polymerase II	TAS PMID:9556563 Ciao 1 is a novel WD40 protein that interacts with the tumor...	KEEP AS NON CORE	Summary: The original 1998 CIAO1 paper identified it as a WT1-interacting protein that modulates WT1 transactivation activity. However, this was before CIAO1's primary role in Fe-S cluster assembly was understood. The effect on transcription is likely indirect through Fe-S protein maturation. Reason: While CIAO1 was originally identified as interacting with WT1 and modulating its transcriptional activity (PMID:9556563), this is now understood as a secondary/indirect effect. CIAO1's primary function is in the CIA pathway for Fe-S cluster assembly. The transcriptional effects may relate to Fe-S cluster-dependent transcription factors or chromatin modifiers. Supporting Evidence: PMID:9556563 Ciao 1 appears to specifically modulate the transactivation activity of WT1
GO:0140132 iron-sulfur cluster chaperone activity	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:23891004 The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins PMID:38950322 CIAO1 is a key component of the CIA machinery

Gene Description

Existing Annotations Review

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References

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Deep Research

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