Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: FANCD2 is a predominantly nuclear protein that concentrates in nuclear foci during S phase and genotoxic stress; the phylogenetic (IBA) nuclear localization is well supported. Reason: Nuclear localization is firmly established experimentally and by UniProt subcellular location, and is consistent with FANCD2's chromatin-associated DNA repair function.
GO:0007129 homologous chromosome pairing at meiosis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: A meiotic role (promoting accurate pairing of homologs) is inferred phylogenetically and supported by high FANCD2 expression in maturing spermatocytes and fetal oocytes, but this is a germline-restricted, non-core activity relative to the somatic ICL-repair function. Reason: Meiotic pairing is a genuine but tissue-restricted function derived from model-organism orthologs; it is peripheral to the central FA-pathway ICL-repair role in somatic cells. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Highly expressed in testis, where expression is restricted to maturing spermatocytes.
GO:0031573 mitotic intra-S DNA damage checkpoint signaling	IBA GO_REF:0000033	ACCEPT	Summary: FANCD2 participates in the S-phase (intra-S) DNA damage checkpoint; ATM phosphorylation of Ser222 is required for checkpoint activation, and the ATR-NBS1-FANCD2 axis mediates the crosslink-induced S-phase checkpoint. Reason: The intra-S checkpoint function is documented experimentally and is an integral part of FANCD2's replication-stress response, consistent with the phylogenetic annotation. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Phosphorylation on Ser-222 is required for S-phase checkpoint activation, but not for ubiquitination, foci formation, or DNA repair
GO:0036297 interstrand cross-link repair	IBA GO_REF:0000033	ACCEPT	Summary: Interstrand crosslink repair is the defining, core biological process of FANCD2; the monoubiquitinated FANCI-FANCD2 complex is required for replication-coupled ICL repair. Reason: This is the central, best-supported function of FANCD2 and is correctly annotated at the appropriate level of specificity. Supporting Evidence: PMID:19965384 FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
GO:1990918 double-strand break repair involved in meiotic recombination	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: A meiotic double-strand-break-repair role is inferred phylogenetically. FANCD2 clearly participates in somatic DSB repair by homologous recombination, but the specifically meiotic recombination context is germline-restricted and non-core. Reason: The general DSB/HR repair activity is core, but the meiotic-recombination-specific term is a tissue-restricted specialization derived from orthologs; retain as non-core.
GO:0000793 condensed chromosome	IBA GO_REF:0000033	ACCEPT	Summary: FANCD2 localizes to condensed mitotic chromosomes, appearing as paired foci on sister-chromatid arms at common fragile sites and at ultrafine anaphase bridges. Reason: Mitotic-chromosome localization is experimentally documented and consistent with FANCD2's role in protecting missegregating chromatin after replication stress. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Observed in a few spots localized in pairs on the sister chromatids of mitotic chromosome arms and not centromeres
GO:0070182 DNA polymerase binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: FANCD2 physically and functionally interacts with the translesion/HR polymerase POLN; DNA polymerase binding is a real but peripheral molecular activity relative to the core DNA-binding clamp scaffold function. Reason: The interaction with POLN is genuine and more informative than generic protein binding, but it is an accessory activity supporting downstream translesion synthesis rather than FANCD2's core function. Supporting Evidence: PMID:19995904 we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Electronic mapping from the UniProt subcellular-location vocabulary places FANCD2 in the nucleus, consistent with all experimental evidence. Reason: Nuclear localization is well established; the IEA mapping is correct.
GO:0006281 DNA repair	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-to-GO electronic annotation places FANCD2 in the broad DNA repair process; this parent term is correct though less specific than interstrand cross-link repair. Reason: DNA repair is a correct, appropriately conservative parent term for FANCD2; the more specific child term (ICL repair) is also annotated.
GO:0005515 protein binding	IPI PMID:12874027 Menin associates with FANCD2, a protein involved in repair o...	MARK AS OVER ANNOTATED	Summary: This IPI records the FANCD2-MEN1 (menin) interaction. Protein binding is an uninformative molecular-function term; the interaction is captured in the notes and does not define a specific FANCD2 activity. Reason: GO:0005515 is too generic for curation. The menin interaction (enhanced by gamma-irradiation) is real but does not correspond to a defined FANCD2 molecular function. Supporting Evidence: PMID:12874027 menin specifically interacts with FANCD2, a protein encoded by a gene involved in DNA repair
GO:0005515 protein binding	IPI PMID:15115758 Direct interaction of FANCD2 with BRCA2 in DNA damage respon...	MARK AS OVER ANNOTATED	Summary: This IPI records the direct FANCD2-BRCA2 interaction that links FANCD2 to homologous recombination. The interaction is biologically important but protein binding is an uninformative MF term. Reason: GO:0005515 is too generic. The BRCA2 interaction is retained as evidence for FANCD2's role in HR-mediated repair (captured in core functions/notes) rather than as a generic binding annotation. Supporting Evidence: PMID:15115758 FANCD2 and BRCA2 can be coimmunoprecipitated from cell extracts of both human and Chinese hamster wild-type cells
GO:0005515 protein binding	IPI PMID:17460694 FANCI is a second monoubiquitinated member of the Fanconi an...	MARK AS OVER ANNOTATED	Summary: This IPI records the interaction with FANCI, FANCD2's obligate partner in the ID2 complex. Although central to FANCD2 biology, protein binding is uninformative as an MF and the ID2 complex membership is annotated separately. Reason: GO:0005515 is too generic. FANCI partnership is captured by the DNA repair (ID2) complex annotation and core functions, not by a generic binding term. Supporting Evidence: PMID:17460694 the discovery of FANCI, a second monoubiquitinated component of the FA pathway
GO:0005515 protein binding	IPI PMID:18212739 FANCG promotes formation of a newly identified protein compl...	MARK AS OVER ANNOTATED	Summary: This IPI records the FANCD2-BRCA2 interaction within a FANCG/XRCC3-containing complex. Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic; the FANCG-dependent BRCA2-FANCD2-XRCC3 complex is relevant to HR but does not define a specific FANCD2 molecular function. Supporting Evidence: PMID:18212739 phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2
GO:0005515 protein binding	IPI PMID:19609304 MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability...	MARK AS OVER ANNOTATED	Summary: This IPI records interaction with the MRE11-RAD50-NBS1 (MRN) complex, which regulates FANCD2 stability and function at DSBs. Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic. The MRN relationship is captured as a regulatory interaction in the notes; it does not correspond to a defined FANCD2 molecular activity. Supporting Evidence: PMID:19609304 Our data establish MRN as a crucial regulator of FANCD2 stability and function in the DNA damage response.
GO:0005515 protein binding	IPI PMID:20603015 Identification of KIAA1018/FAN1, a DNA repair nuclease recru...	MARK AS OVER ANNOTATED	Summary: This IPI records interactions from the FAN1 discovery study (including FAN1/MTMR15 recruited by monoubiquitinated FANCD2). Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic. FAN1 recruitment by monoubiquitinated FANCD2 is a key mechanistic finding but is best represented through process/complex annotations rather than generic binding. Supporting Evidence: PMID:20603015 KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2
GO:0005515 protein binding	IPI PMID:20805509 CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-med...	MARK AS OVER ANNOTATED	Summary: This IPI records the FANCD2-CEBPD interaction that, via IPO4, promotes nuclear import and monoubiquitination of FANCD2. Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic; the CEBPD/IPO4 interaction is an upstream regulatory step for FANCD2 activation, not a FANCD2 molecular function. Supporting Evidence: PMID:20805509 augmenting nuclear import of FANCD2, a prerequisite for its monoubiquitination
GO:0005515 protein binding	IPI PMID:35384245 Physical and functional interactome atlas of human receptor ...	MARK AS OVER ANNOTATED	Summary: This IPI derives from a high-throughput receptor tyrosine kinase interactome atlas reporting an EGFR interaction. Protein binding is uninformative and this proteome-scale interaction has no established FANCD2 functional context. Reason: GO:0005515 is too generic and this high-throughput EGFR interaction is not connected to any characterized FANCD2 molecular function.
GO:0005515 protein binding	IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei...	MARK AS OVER ANNOTATED	Summary: This IPI derives from a systematic screen for mutation-directed neo-protein-protein interactions in cancer (EGFR). Protein binding is uninformative and lacks established FANCD2 functional relevance. Reason: GO:0005515 is too generic; the reported neo-interaction has no characterized bearing on FANCD2's core biology.
GO:0000785 chromatin	NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN...	ACCEPT	Summary: FANCD2 associates with chromatin in a monoubiquitination-dependent manner; chromatin retention is required for its DNA-repair function. Reason: Chromatin localization is well established and mechanistically central (ubiquitination is required for chromatin binding); the ComplexPortal NAS annotation is appropriate. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Ubiquitination is required for binding to chromatin, interaction with BRCA1, BRCA2 and MTMR15/FAN1, DNA repair, and normal cell cycle progression
GO:0036297 interstrand cross-link repair	NAS PMID:19965384 The Fanconi anemia pathway promotes replication-dependent DN...	ACCEPT	Summary: ICL repair is FANCD2's core biological process; the FANCI-FANCD2 complex is required for replication-coupled ICL repair, with FANCD2 removal blocking both incision and translesion synthesis. Reason: Correct, well-supported core-process annotation; consistent with the IBA annotation of the same term. Supporting Evidence: PMID:19965384 Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion.
GO:1990391 DNA repair complex	IPI PMID:32269332 DNA clamp function of the monoubiquitinated Fanconi anaemia ...	ACCEPT	Summary: FANCD2 is a subunit of the FANCI-FANCD2 (ID2) DNA-repair complex; the monoubiquitinated ID2 complex forms a closed ring that encircles DNA and acts as a sliding clamp. Reason: Membership in the ID2 DNA-repair complex is central to FANCD2 function and is directly supported by cryo-EM structural work. Supporting Evidence: PMID:32269332 The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence (HPA) localizes FANCD2 to the nucleoplasm, consistent with its diffuse nuclear distribution outside of damage-induced foci. Reason: Nucleoplasmic localization is consistent with established nuclear localization and the numerous concordant annotations.
GO:0005730 nucleolus	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence reports FANCD2 in the nucleolus. A nucleolar pool has been described, but this is a minor/context-dependent localization relative to the nucleoplasmic and chromatin pools that carry out ICL repair. Reason: Nucleolar localization is plausible but peripheral to FANCD2's core chromatin-associated DNA-repair function; retain as non-core.
GO:0016604 nuclear body	IDA GO_REF:0000052	ACCEPT	Summary: FANCD2 concentrates into damage-induced nuclear foci (nuclear bodies) during S phase and after genotoxic stress, a hallmark of its activation. Reason: Nuclear-focus (nuclear body) localization is a well-documented, functionally meaningful feature of activated FANCD2. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Concentrates in nuclear foci during S phase and upon genotoxic stress
GO:0005634 nucleus	EXP PMID:30335751 Identification of UHRF2 as a novel DNA interstrand crosslink...	ACCEPT	Summary: FANCD2 is recruited to and retained on chromatin at ICLs in the nucleus, cooperating with UHRF1/UHRF2 for its activation. Reason: Experimental evidence supports nuclear/chromatin localization; consistent with all other nuclear annotations. Supporting Evidence: PMID:30335751 The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785342	ACCEPT	Summary: Reactome places FANCD2 in the nucleoplasm within the FANCD2-FANCI/UBE2T ICL-DNA binding step of the FA pathway. Reason: Author-stated nucleoplasmic localization consistent with FANCD2 nuclear biology and the FA pathway reaction context.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785361	ACCEPT	Summary: Reactome nucleoplasmic localization for the monoubiquitination-of-FANCD2/FANCI reaction. Reason: Consistent with FANCD2's established nucleoplasmic localization during FA-pathway activation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785594	ACCEPT	Summary: Reactome nucleoplasmic localization for the FANCD2-binds-FANCI reaction. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785732	ACCEPT	Summary: Reactome nucleoplasmic localization for DNA nucleases binding the monoubiquitinated ID2 complex. Reason: Consistent with FANCD2's established nucleoplasmic localization within the ICL-repair reaction context.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6785986	ACCEPT	Summary: Reactome nucleoplasmic localization for the nuclease-mediated unhooking of the ICL step. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786155	ACCEPT	Summary: Reactome nucleoplasmic localization for the POLN-binds-ICL-DNA step of the FA pathway. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786166	ACCEPT	Summary: Reactome nucleoplasmic localization for the POLN translesion-synthesis step. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6786171	ACCEPT	Summary: Reactome nucleoplasmic localization for the FANCD2 deubiquitination by USP1/WDR48 step. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788385	ACCEPT	Summary: Reactome nucleoplasmic localization for the ATR/ATRIP recruitment to ICL-DNA step. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6788392	ACCEPT	Summary: Reactome nucleoplasmic localization for the ATR phosphorylation of RPA2/FANCI/FANCD2/FANCM step. Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6797712	ACCEPT	Summary: Reactome nucleoplasmic localization associated with CDK12 stimulation of DNA repair gene expression (FA pathway context). Reason: Consistent with FANCD2's established nucleoplasmic localization.
GO:0005634 nucleus	IDA PMID:26323318 NUCKS1 is a novel RAD51AP1 paralog important for homologous ...	ACCEPT	Summary: Direct-assay nuclear localization of FANCD2, consistent with all other evidence for a nuclear protein. Reason: Nuclear localization is firmly established; the IDA annotation is correct. Supporting Evidence: PMID:26323318 the levels of soluble nuclear and chromatin-associated ATM, FANCD2
GO:0070182 DNA polymerase binding	IPI PMID:19995904 DNA polymerase POLN participates in cross-link repair and ho...	KEEP AS NON CORE	Summary: FANCD2 interacts with the DNA polymerase POLN, which participates in crosslink repair and homologous recombination downstream of FA-pathway activation. This is a genuine but peripheral molecular activity. Reason: DNA polymerase (POLN) binding is more informative than generic protein binding and is experimentally supported, but represents an accessory interaction rather than FANCD2's core DNA-binding clamp function; consistent with the IBA annotation of the same term. Supporting Evidence: PMID:19995904 we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway
GO:0005515 protein binding	IPI PMID:20603016 Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensi...	MARK AS OVER ANNOTATED	Summary: This IPI records a FAN1-related interaction from a study showing FAN1 deficiency sensitizes cells to crosslinking agents. Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic. The FAN1 relationship is captured through FANCD2's ICL-repair process annotations rather than a generic binding term.
GO:0005515 protein binding	IPI PMID:20603073 A genetic screen identifies FAN1, a Fanconi anemia-associate...	MARK AS OVER ANNOTATED	Summary: This IPI records a FAN1-related interaction from a genetic screen identifying FAN1 as an FA-associated nuclease. Protein binding is uninformative as an MF term. Reason: GO:0005515 is too generic; the FAN1 nuclease relationship is represented through process/complex annotations, not a generic binding term.
GO:0010332 response to gamma radiation	IDA PMID:12874027 Menin associates with FANCD2, a protein involved in repair o...	KEEP AS NON CORE	Summary: FANCD2 responds to ionizing/gamma radiation (ATM-dependent Ser222/Ser1404 phosphorylation and foci formation); in this study the FANCD2-menin interaction was enhanced by gamma-irradiation. Reason: Responsiveness to gamma radiation is a real facet of FANCD2's DNA-damage response but is a downstream/secondary aspect relative to its core replication-coupled ICL-repair function. Supporting Evidence: PMID:12874027 The interaction between menin and FANCD2 is enhanced by gamma-irradiation.
GO:0003697 single-stranded DNA binding	IDA PMID:19609304 MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability...	NEW	Summary: Purified FANCD2 is a ring-like particle that preferentially binds single-stranded DNA over other substrates, consistent with its DNA-binding scaffold/clamp role in repair. This molecular-function is missing from the current GOA set (which lists only generic protein binding and DNA polymerase binding). Reason: A defined DNA-binding molecular function is needed to represent FANCD2's core biochemical activity; direct in vitro evidence supports single-stranded DNA binding. Supporting Evidence: PMID:19609304 Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates.
GO:0000724 double-strand break repair via homologous recombination	ISS PMID:15601828 Fanconi anemia protein FANCD2 promotes immunoglobulin gene c...	NEW	Summary: FANCD2 promotes homologous-recombination repair of DNA double-strand breaks; the FA monoubiquitination pathway is required for efficient HR, and FANCD2 loads BRCA2/FANCD1 onto damaged chromatin. The direct loss-of-function evidence quoted below is from a CHICKEN DT40 fancd2 line, not from human cells. This core HR-repair process is not explicitly captured by the existing GOA terms. Reason: FANCD2's role in double-strand break repair by homologous recombination is well documented and is a core process underlying its ICL-repair and genome-stability functions, but the primary loss-of-function experiment is in chicken DT40 cells, so the code is ISS rather than IMP - an IMP would assert a human mutant phenotype that this reference does not provide. original_reference_id changed from the derived FANCD2-uniprot.txt to the primary paper, since a UniProt flat file is not a valid basis for an author-supplied experimental-evidence annotation. Supporting Evidence: file:human/FANCD2/FANCD2-uniprot.txt Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing PMID:15601828 FANCD2-disrupted DT40 chicken B-cell line is defective in HR-mediated DNA double-strand break (DSB) repair, as well as gene conversion at the immunoglobulin light-chain locus
GO:0031297 replication fork processing	IMP PMID:25659033 FANCD2, FANCJ and BRCA2 cooperate to promote replication for...	NEW	Summary: Beyond ICL repair, FANCD2 protects and promotes recovery of stalled replication forks. Non-ubiquitinated FANCD2 acts with the BLM helicase complex to restart aphidicolin-stalled forks while suppressing new origin firing, and monoubiquitinated FANCD2 recruits the FAN1 nuclease to restrain fork progression and prevent chromosome abnormalities even in the absence of crosslinks. This core genome-maintenance activity is described in the review narrative but is not otherwise captured by a GOA term. Reason: Replication fork protection/restart is a well-documented FANCD2 function, distinct from and partly independent of the canonical monoubiquitination/ICL-repair role; GO:0031297 (replication fork processing, restoration and restart of stalled forks) is the appropriate specific process term. Supporting Evidence: PMID:25659033 it binds chromatin and acts in concert with the BLM helicase complex to promote the restart of aphidicolin (APH)-stalled replication forks, while suppressing the firing of new replication origins PMID:26797144 restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs
GO:0062176 R-loop processing	IMP PMID:30431240 FANCD2 protects genome stability by recruiting RNA processin...	NEW	Summary: FANCD2 suppresses R-loop (RNA-DNA hybrid) accumulation during replication stress by recruiting RNA-processing factors (hnRNP U, DDX47) to R-loop-containing chromatin and, with SRSF1, promoting mRNA export; this reduces transcription-replication collisions and preserves genome stability. This genome-protective activity is not represented in the current GOA set. Reason: R-loop suppression is a genuine, experimentally supported secondary function of FANCD2 (independent studies converge on it); GO:0062176 (R-loop processing, disassembly/resolution of R-loops) is the correctly branched process term. Non-core relative to ICL repair but well evidenced. Supporting Evidence: PMID:30431240 we found that FANCD2 suppresses R-loop levels. Furthermore, we identified FANCD2 interactions with RNA processing factors, including hnRNP U and DDX47 PMID:38165804 Defects in the FA pathway lead to R-loop accumulation, which contributes to genomic instability
GO:0005739 mitochondrion	ISO PMID:28378742 Fancd2 in vivo interaction network reveals a non-canonical r...	NEW	Summary: A mitochondrial pool of Fancd2 has been reported IN MOUSE, in which Fancd2 localizes to mitochondria and associates with the nucleoid components Atad3 and Tufm, whose complex is disrupted in Fancd2-/- cells, implicating Fancd2 in a non-canonical mitochondrial homeostasis role. PMID:28378742 is a mouse-only study (Fancd2 3xFLAG/HA knock-in mouse, MEFs and mouse organs); there is no human observation of this pool, so the human annotation is by orthology only. Peripheral to the nuclear DNA-repair function. Reason: Mitochondrial localization is experimentally documented, but only for the mouse ortholog, so the evidence code is ISO (with UniProtKB:Q80V54, mouse Fancd2) rather than IDA - an IDA here would assert a direct human observation that does not exist. Non-canonical and non-core relative to FANCD2's central nuclear ICL-repair function; added as a secondary localization for completeness, explicitly flagged as mouse-derived. Supporting Evidence: PMID:28378742 Fancd2 localizes in the mitochondrion and associates with the nucleoid complex components Atad3 and Tufm

Core Functions

With its paralog FANCI, FANCD2 forms the ID2 DNA-repair complex that binds DNA and, upon FANCL/UBE2T-catalyzed monoubiquitination at Lys561, is remodeled into a closed sliding clamp encircling duplex DNA. FANCD2 itself preferentially binds single-stranded DNA. This chromatin-loaded, DNA-binding clamp scaffold coordinates the core steps of replication-coupled interstrand crosslink repair (nucleolytic incision, translesion synthesis) and homologous recombination, and recruits downstream factors such as the nuclease FAN1.

Molecular Function:

single-stranded DNA binding

Directly Involved In:

interstrand cross-link repair double-strand break repair via homologous recombination replication fork processing mitotic intra-S DNA damage checkpoint signaling

Cellular Locations:

chromatin nucleoplasm

In Complex:

DNA repair complex

Supporting Evidence:

PMID:19609304
Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates.
PMID:32269332
the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions
PMID:19965384
FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.

References

file:human/FANCD2/FANCD2-uniprot.txt

UniProtKB entry Q9BXW9 (FACD2_HUMAN), Fanconi anemia group D2 protein

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:12874027

Menin associates with FANCD2, a protein involved in repair of DNA damage.

PMID:15115758

Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.

PMID:17460694

FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.

PMID:18212739

FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.

PMID:19609304

MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability and function during DNA double-strand break repair.

PMID:19965384

The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

PMID:19995904

DNA polymerase POLN participates in cross-link repair and homologous recombination.

PMID:20603015

Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.

PMID:20603016

Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.

PMID:20603073

A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.

PMID:20805509

CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage.

PMID:26323318

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability.

PMID:30335751

Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein.

PMID:32269332

DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.

PMID:35384245

Physical and functional interactome atlas of human receptor tyrosine kinases.

PMID:35512704

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.

PMID:15601828

Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and DNA repair through a mechanism related to homologous recombination.

PMID:25659033

FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex.

PMID:26797144

Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability.

PMID:30431240

FANCD2 protects genome stability by recruiting RNA processing enzymes to resolve R-loops during mild replication stress.

PMID:38165804

The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export.

PMID:28378742

Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial function.

Reactome:R-HSA-6785342

FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex

Reactome:R-HSA-6785361

Monoubiquitination of FANCD2:FANCI

Reactome:R-HSA-6785594

FANCD2 binds FANCI

Reactome:R-HSA-6785732

DNA nucleases bind monoubiquitinated ID2 complex

Reactome:R-HSA-6785986

DNA nucleases unhook the interstrand crosslink (ICL)

Reactome:R-HSA-6786155

POLN binds ICL-DNA

Reactome:R-HSA-6786166

Translesion synthesis across unhooked ICL by POLN

Reactome:R-HSA-6786171

FANCD2 deubiquitination by USP1:WDR48

Reactome:R-HSA-6788385

The complex of ATR and ATRIP is recruited to ICL-DNA

Reactome:R-HSA-6788392

ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA

Reactome:R-HSA-6797712

CDK12 stimulates expression of DNA repair genes

Suggested Experiments

Experiment: Separation-of-function alleles (Lys561 ubiquitination-dead and DNA-binding mutants) assayed for ICL incision, translesion synthesis, HR, and fork protection to map which activities require the sliding-clamp conformation.

Experiment: Genome-wide mapping (ChIP-seq or CUT-and-RUN) of chromatin-bound versus monoubiquitinated FANCD2 under replication stress to define its DNA-structure and locus preferences relative to common fragile sites.

Deep Research

Affinage

(FANCD2-deep-research-affinage.md)

Affinage mechanistic annotation for FANCD2 (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 60 citations

Affinage mechanistic annotation for FANCD2 (human)

Current model (mechanistic narrative)

FANCD2 is the central effector of the Fanconi anemia (FA) DNA repair pathway, originally identified by positional cloning as the FA-D2 gene product whose reintroduction complements mitomycin C sensitivity in patient cells PMID:11239453. Its activation is governed by a regulated cycle of post-translational modification: ATR/ATM kinases phosphorylate FANCD2 (T691, S717) and its partner FANCI, priming the complex [PMID:16943440, PMID:36050501], after which the FA core complex — minimally the FANCB-FANCL-FAAP100 module using UBE2T as E2 — monoubiquitinates FANCD2 on K561 during S phase and in response to DNA damage [PMID:12239151, PMID:24905007, PMID:31873223]. This modification drives translocation from soluble nucleoplasm to chromatin, where FANCD2 forms damage-induced foci with BRCA1 and RAD51 [PMID:12239151, PMID:15454491]. FANCD2 functions as an obligate heterodimer with its paralog FANCI, and DNA engagement by the ID2 complex is required for efficient monoubiquitination [PMID:17412408, PMID:22287633, PMID:24623813]. Structural studies establish that the unmodified ID2 complex is recruited to DNA and that monoubiquitination triggers a conformational closure into a sliding clamp that encircles dsDNA, with ubiquitin acting as a molecular pin at the I-D interface; the clamp diffuses on duplex DNA and stalls at ssDNA-dsDNA junctions found at stalled replication forks [PMID:21764741, PMID:32066963, PMID:32510829, PMID:39085614]. Activated FANCD2 coordinates interstitial crosslink repair by recruiting the XPF-ERCC1/SLX4 nucleases for unhooking incisions, FAN1 and CtIP for end processing and resection, and by stabilizing RAD51 filaments and mediating strand exchange while protecting DNA ends from DNA2, MRE11, and EXO1 nucleases [PMID:20603015, PMID:24726325, PMID:24794430, PMID:24794434, PMID:27694619, PMID:37526271]. The cycle is reversed by USP1-UAF1, which deubiquitinates K561 in a DNA- and FANCI-contact-dependent manner requiring a FANCD2-specific sequence in the USP1 N-terminus [PMID:18082605, PMID:31253762, PMID:33795880]. Beyond crosslink repair, FANCD2 — including its non-ubiquitinated form — restrains replication fork progression at common fragile sites and in BRCA1/2-deficient cells where its loss is synthetic lethal, suppresses R-loop accumulation by recruiting RNA-processing factors and collaborating with SRSF1 for mRNA export, activates TAp63 transcription to suppress skin carcinogenesis, and localizes to mitochondria where it supports homeostasis through ATAD3 and TUFM [PMID:23806336, PMID:26797144, PMID:27768874, PMID:27264184, PMID:28378742, PMID:30431240, PMID:38165804].

Affinage mechanism profile (Affinage's own GO/Reactome grounding)

molecular_activity: GO:0003677 DNA binding, GO:0003723 RNA binding, GO:0031386 protein tag activity, GO:0140096 catalytic activity, acting on a protein, GO:0060090 molecular adaptor activity, GO:0140110 transcription regulator activity
localization: GO:0005634 nucleus, GO:0000228 nuclear chromosome, GO:0005654 nucleoplasm, GO:0005739 mitochondrion
pathway (Reactome): R-HSA-73894 DNA Repair, R-HSA-69306 DNA Replication, R-HSA-1640170 Cell Cycle, R-HSA-8953854 Metabolism of RNA
partners: FANCI, FANCL, USP1, UAF1, FAN1, CTIP, RAD51, BRCA2
complexes: FANCI-FANCD2 (ID2) complex

Dated findings (citation-anchored)

Year	Confidence	Finding	PMIDs	Journal
2001	High	FANCD2 encodes a novel 1451 amino acid nuclear protein with two isoforms; retroviral transduction of FANCD2 cDNA into FA-D2 cells complemented MMC sensitivity, establishing it as the FA-D2 gene product functioning in DNA crosslink repair.	PMID:11239453	Molecular cell
2002	High	FANCD2 undergoes monoubiquitination on K561 during S phase and in response to DNA damage; monoubiquitinated FANCD2 colocalizes with BRCA1 and RAD51 in S-phase nuclear foci, and this monoubiquitination is required for normal cell-cycle progression after MMC treatment.	PMID:12239151	Blood
2002	High	FANCD2 and NBS1 colocalize in subnuclear foci after MMC treatment; ionizing radiation activates ATM- and NBS1-dependent phosphorylation of FANCD2, establishing an S-phase checkpoint function, and NBS1 cells are hypersensitive to MMC.	PMID:12447395	Nature cell biology
2003	High	BRCA1/BARD1 complex can reconstitute FANCD2 monoubiquitination in vitro, but siRNA knockdown of BRCA1 or ablation of BRCA1/BARD1 RING finger domains in DT40 cells does not impair FANCD2 ubiquitination; BRCA1 affects chromatin targeting of FANCD2 but is not the essential E3 ligase for FANCD2 monoubiquitination.	PMID:12887909	Molecular cell
2003	Medium	Menin (MEN1 product) specifically interacts with FANCD2, and this interaction is enhanced by gamma-irradiation; loss of menin in mouse embryonic fibroblasts increases sensitivity to DNA damage, placing menin in the FANCD2-dependent DNA repair pathway.	PMID:12874027	Cancer research
2004	High	ATR kinase and RPA1 are required for efficient FANCD2 monoubiquitination; deficiency of ATR (Seckel syndrome cells or siRNA silencing) results in radial chromosomes after MMC treatment, mimicking FA chromosome instability.	PMID:15314022	Genes & development
2004	Medium	FANCD2 directly interacts with BRCA2 via a conserved C-terminal site also bound by FANCG/XRCC9; this interaction was confirmed by co-immunoprecipitation from human and hamster cell extracts. FANCD2 focus formation is independent of BRCA2. FANCD2 colocalizes with RAD51 after MMC or hydroxyurea treatment and very tightly with PCNA after hydroxyurea.	PMID:15115758	Human molecular genetics
2004	High	Monoubiquitination of FANCD2 on K561 is required for its translocation from the soluble nuclear compartment to chromatin; the C-terminal residue D1428 (encoded by exon 44) is independently required for functional complementation of FA-D2 cells even when monoubiquitination and chromatin binding are intact.	PMID:15454491	Blood
2004	High	In Xenopus egg extracts, linear and branched double-stranded DNA (but not single-stranded or Y-shaped DNA) rapidly triggers FANCD2 monoubiquitination in an FA core complex-dependent but ATRIP-independent manner, and monoubiquitinated FANCD2 associates with these DNA structures.	PMID:17420278	Molecular and cellular biology
2005	High	FANCD2-disrupted DT40 cells are defective in HR-mediated DSB repair and immunoglobulin gene conversion; they show increased sister chromatid exchange and intact Rad51 foci, indicating FANCD2 promotes a subpathway of HR that mediates gene conversion via a mechanism avoiding crossovers.	PMID:15601828	Molecular and cellular biology
2006	High	ATR phosphorylates FANCD2 on T691 and S717; these phosphorylations promote FANCD2 monoubiquitination and enhance cellular resistance to DNA crosslinking agents and intra-S-phase checkpoint establishment. ATM also phosphorylates these sites in response to IR.	PMID:16943440	Molecular and cellular biology
2006	Medium	Drosophila FANCD2 and FANCL function in a linear pathway in which FANCL is necessary for FANCD2 monoubiquitination; FANCD2 mutants show defects in the IR-inducible S-phase checkpoint and elevated mutation rates after nitrogen mustard, establishing conservation of FA pathway function.	PMID:16860002	DNA repair
2007	High	FANCI is a monoubiquitinated paralog of FANCD2 that forms the FANCI-FANCD2 (ID) complex; the two proteins associate and localize together to chromatin in response to DNA damage. Monoubiquitination of each protein is important for maintaining ubiquitin on the other (dual ubiquitin-locking mechanism), and FANCI mutation causes FA complementation group I.	PMID:17412408	Cell
2007	High	USP1 ablation in DT40 cells results in constitutively chromatin-bound monoubiquitinated FANCD2 and DNA crosslinker sensitivity, demonstrating that FANCD2 deubiquitination (not just ubiquitination) is required for efficient DNA crosslink repair; persistent PCNA monoubiquitination has negligible impact on DNA repair.	PMID:18082605	Molecular cell
2007	Medium	The FA core complex and UBE2T are independently recruited to chromatin; E3 ligase activity is regulated by DNA damage-induced chromatin localization of the complex, not by complex assembly; FANCD2 accesses chromatin independently of the FA core complex.	PMID:17938197	Molecular and cellular biology
2007	High	FANCL interacts with FANCD2 via its PHD domain (yeast two-hybrid and Co-IP); FANCL is required for FANCD2 monoubiquitination and focus formation; FANCL and monoubiquitination of FANCD2 K563 are both required for HR repair of I-SceI-induced DSBs at equivalent quantitative levels.	PMID:17352736	Genes to cells
2008	Medium	FANCG phosphorylation on serine 7 is required for co-precipitation of a BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3) complex; direct BRCA2-FANCD2 interaction requires FANCG and its S7 phosphorylation; FANCG and XRCC3 are epistatic for sensitivity to DNA crosslinking agents in DT40 cells.	PMID:18212739	Oncogene
2009	High	FANCI directly binds DNA and forms a stable complex with FANCD2 via FANCI's C-terminal region (aa 1001–1328); the FANCI-FANCD2 complex preferentially binds branched DNA structures compared to each protein alone, suggesting recognition of damaged replication forks.	PMID:19561358	The Journal of biological chemistry
2009	Medium	Inhibition of MRE11, NBS1, or RAD50 destabilizes FANCD2; purified FANCD2 is a ring-like particle by EM that preferentially binds ssDNA; inhibition of MRE11 nuclease activity decreases FANCD2 foci, indicating MRN complex is a crucial regulator of FANCD2 stability and promotes FANCD2 binding to ssDNA at MRN-processed DSBs.	PMID:19609304	The EMBO journal
2009	Medium	In Xenopus egg extracts, FANCM chromatin binding and DNA damage-induced phosphorylation are controlled in part by the downstream FA pathway protein FANCD2, as well as by ATR and ATM kinases.	PMID:19633289	The Journal of biological chemistry
2010	High	Monoubiquitinated FANCD2 recruits FAN1 (KIAA1018) to sites of DNA damage; FAN1 is a nuclease with 5' flap endonuclease and 5' exonuclease activities mediated by a VRR_nuc domain; FAN1 depletion causes ICL hypersensitivity and genome instability.	PMID:20603015	Cell
2011	High	Crystal structure of the ~300 kDa FANCI-FANCD2 (ID) complex at 3.4 Å reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting these modifications occur on monomeric proteins or an opened complex and may stabilize heterodimerization. Each protein has binding sites for both ssDNA and dsDNA, suggesting the ID complex recognizes DNA structures at replication fork-ICL encounters.	PMID:21764741	Science
2011	Medium	RAD18 binds FANCD2 (RING domain-dependent) and is required for efficient monoubiquitylation and chromatin localization of both FANCD2 and FANCI; RAD18 knockout cells show delayed FANCD2 foci formation and ICL sensitivity. FANCD2 ubiquitylation is normal in PCNA ubiquitylation-resistant cells, indicating RAD18 acts independently of PCNA ubiquitylation.	PMID:21355096	Blood
2012	High	Various forms of DNA (ssDNA, dsDNA, branched DNA) robustly stimulate FANCD2 monoubiquitylation in vitro up to near-in-vivo levels; this DNA stimulation strictly requires FANCI and FANCI's DNA-binding activity, demonstrating that FANCD2 monoubiquitination occurs within the FANCI-FANCD2 complex and requires DNA engagement.	PMID:22287633	Nucleic acids research
2012	Medium	FANCD2 contains a CUE ubiquitin-binding domain that mediates noncovalent ubiquitin binding in vitro; the CUE domain is required for interaction with FANCI, chromatin retention of monoubiquitinated FANCD2 and FANCI, and efficient ICL repair, suggesting FANCD2 CUE domain noncovalently binds the ubiquitin on FANCI to stabilize the complex on chromatin.	PMID:22855611	Blood
2013	High	FANCD2 directly interacts with MCM2-MCM7 replicative helicase; ATR signaling promotes transient association of endogenous FANCD2 with MCM2-7 independently of FANCD2 monoubiquitination; FANCD2 restrains DNA synthesis under nucleotide-limiting conditions and prevents ssDNA accumulation and senescence entry.	PMID:23993743	Molecular cell
2013	High	Monoubiquitinated FANCD2 activates transcription of the tumor suppressor TAp63, promoting cellular senescence and blocking skin tumorigenesis; Usp1-deficient mice with elevated FANCD2-Ub are resistant to skin tumors while Fancd2-deficient mice are prone to Ras-driven skin carcinogenesis.	PMID:23806336	Molecular cell
2013	Medium	mTOR regulates FANCD2 expression via NF-κB; mTOR deficiency or inhibition increases NF-κB nuclear translocation, enhancing NF-κB binding to the FANCD2 promoter to suppress FANCD2 expression; exogenous FANCD2 rescues the DNA damage response defect in mTOR-inhibited cells.	PMID:23538752	Leukemia
2014	High	Biochemical reconstitution of FANCD2 monoubiquitination using purified native avian FA core complex demonstrates that FANCL must be embedded in the complex for maximal activity and site specificity; a minimal subcomplex of FANCB-FANCL-FAAP100 is sufficient as the monoubiquitination module; cells defective in other subunits retain residual activity.	PMID:24905007	Molecular cell
2014	High	XPF-ERCC1 cooperates with SLX4/FANCP to perform the DNA unhooking incisions during replication-coupled ICL repair in Xenopus egg extracts; efficient recruitment of XPF-ERCC1 and SLX4 to the ICL depends on FANCD2 and its ubiquitylation.	PMID:24726325	Molecular cell
2014	High	CtIP directly interacts with FANCD2; monoubiquitination of FANCD2 and CtIP residues 166-273 are both required for the FANCD2-CtIP interaction and MMC-induced CtIP foci; FANCD2 and CtIP cooperate to promote RPA2 hyperphosphorylation accompanying DNA end resection at ICL-induced DSBs.	PMID:24794430, PMID:24794434	Cell reports
2014	High	Monoubiquitinated FANCD2 tethers CtIP to damaged chromatin; CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, leading to increased non-homologous end-joining and ICL hypersensitivity; CtIP depletion aggravates genomic instability in FANCD2-deficient cells.	PMID:24794434, PMID:24794430	Cell reports
2014	Medium	CtIP is recruited by FANCD2 to stalled replication forks on chromatin independently of FANCD2 monoubiquitination; CtIP cooperates with FANCD2 to promote fork restart and suppress new origin firing in a BRCA1-dependent manner.	PMID:24556218	Human molecular genetics
2014	High	Regulation of FANCD2 and FANCI monoubiquitination by DNA: duplex or branched DNA strongly stimulates FANCD2 monoubiquitination in the ID2 complex, but unstructured ssDNA or chromatinized DNA is not effective; FANCI DNA-binding mutants compromise FANCD2 ubiquitination; FANCL interaction with the ID2 complex is indispensable for E3 ligase efficacy.	PMID:24623813	Nucleic acids research
2015	Medium	UHRF1 acts upstream of FANCD2 in the FA pathway: UHRF1 directly binds ICLs in vitro and in vivo, is rapidly recruited to chromatin before FANCD2, and its knockdown drastically reduces FANCD2 foci formation, indicating UHRF1 senses ICLs and recruits FANCD2.	PMID:25801034	Cell reports
2015	Medium	FANCD2 promotes replication fork restart and suppresses new origin firing independently of FA core complex-mediated monoubiquitination after aphidicolin treatment; FANCJ and BRCA2 share this replication fork recovery role with non-ubiquitinated FANCD2, independently of the FA core complex.	PMID:25659033	Cell cycle
2016	High	FANCD2-FANCI (ID) complex adopts a closed conformation when FANCD2 is monoubiquitinated, forming a channel that encloses dsDNA; ubiquitin acts as a covalent molecular pin at the FANCD2-FANCI interface to trap the complex on DNA; unmodified FANCD2 forms a homodimer unable to bind DNA, suggesting an autoinhibitory mechanism.	PMID:32066963	Nature structural & molecular biology
2016	High	The FANCD2-FANCI complex is recruited to stalled replication forks (as detected at ICLs) before monoubiquitination; cryo-EM structure of the human FANCD2-FANCI complex shows an inner cavity large enough for dsDNA and a Tower domain; disease-causing mutations in the Tower domain impair FA pathway activation.	PMID:27405460	Nature communications
2016	High	Ubiquitinated FANCD2 recruits FAN1 to stalled replication forks to restrain fork progression and prevent chromosome abnormalities, even in the absence of ICLs; FAN1 nuclease-defective knockin mice are cancer-prone; a cancer-associated FAN1 variant abolishing Ub-FANCD2 binding causes genetic instability without affecting ICL repair.	PMID:26797144	Science
2016	High	FANCD2 acts as a trans-acting facilitator of common fragile site (CFS) replication; in FANCD2-deficient cells, replication forks stall within AT-rich CFS cores leading to dormant origin activation; FANCD2 deficiency is associated with DNA:RNA hybrid formation at CFS-FRA16D, and inhibition of DNA:RNA hybrids suppresses replication perturbation.	PMID:27768874	Molecular cell
2016	High	FANCD2 is required for fork protection and restart in BRCA1/2-deficient tumors; FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair; loss of FANCD2 in BRCA1/2-deficient tumors results in synthetic lethality.	PMID:27264184	Cell reports
2016	Medium	Monoubiquitinated FANCD2 antagonizes the BLM helicase to restrain telomere replication and recombination in ALT cells; FANCD2 depletion causes a hyper-ALT phenotype with increased extrachromosomal telomeric repeat DNAs suppressed by BLM but not RAD51 loss.	PMID:27427384	Human molecular genetics
2016	High	FANCI-FANCD2 complex directly binds RAD51 and stabilizes the RAD51-DNA filament; this DNA end protection from FAN1 nucleolytic degradation requires FANCI's DNA-binding activity (not FANCD2's), and is abolished by the RAD51 mutant from FANCR patient cells.	PMID:27694619	Nucleic acids research
2017	Medium	FANCD2 binds HPV genomes preferentially over cellular chromosomes and is required for maintenance of HPV episomes in undifferentiated basal epithelial cells; HPV-dependent FANCD2 foci colocalize with ATM pathway components (γH2AX, BRCA1) but not p-SMC1.	PMID:28196964	mBio
2017	Medium	FANCD2 interacts with the spliceosomal protein SF3B1 (U2 snRNP component); replication stress induces ATR-dependent release of SF3B1 from nuclear speckles in a FANCI-dependent manner; both FANCD2 and FANCI associate with SF3B1 on chromatin and prevent accumulation of postcatalytic intron lariats.	PMID:29030393	The Journal of cell biology
2017	Medium	FANCD2 localizes to mitochondria where it associates with nucleoid complex components ATAD3 and TUFM; ATAD3-TUFM complex is disrupted in Fancd2-/- and Fanca-/- mice; FANCD2 mitochondrial localization requires ATAD3, suggesting a role in mitochondrial homeostasis.	PMID:28378742	Scientific reports
2017	Low	Monoubiquitinated FANCD2 (but not K561R mutant) interacts with ATP5α; monoubiquitination-dependent localization of ATP5α within mitochondria is required for normal mitochondrial ATP production; loss of monoubiquitinated FANCD2 causes mislocalization of ATP5α and reduced mitochondrial ATP output.	PMID:28687786	Scientific reports
2018	Medium	FANCD2 accumulates at the central regions of large transcribed genes (common fragile sites) during replication stress in an R-loop-dependent manner (as shown by ChIP-seq and PLA); however, FANCD2 monoubiquitination and RPA foci formation are still induced in R-loop-depleted cells, indicating R-loops are needed for FANCD2 retention at chromatin but not for upstream FA pathway activation.	PMID:29394375	Nucleic acids research
2018	Medium	FANCD2 interacts with RNA processing factors hnRNP U and DDX47 and recruits them to R-loop-containing chromatin; this reduces transcription-replication collisions and lowers R-loop levels, contributing to genome stability during mild replication stress.	PMID:30431240	The FEBS journal
2019	High	Purified human FANCI-FANCD2 (ID2) complex binds ssRNA and R-loop substrates with high affinity (preferring G-rich sequences) via recognition of displaced ssDNA and ssRNA; RNA and R-loop substrates strongly stimulate ID2 monoubiquitination in vitro with activity corresponding to binding affinity.	PMID:30650351	Cell reports
2019	High	Efficient FANCD2 deubiquitination by the USP1-UAF1 complex is DNA-dependent and requires DNA binding by UAF1; the DNA-binding activity of the UAF1-associated protein RAD51AP1 can substitute for UAF1 DNA binding in FANCD2 deubiquitination in reconstituted biochemical systems.	PMID:31253762	Nature communications
2019	High	CK2 phosphorylates a cluster of FANCD2 sites to inhibit FANCD2 binding to DNA and thereby prevent FANCD2 recruitment to ICLs and its monoubiquitination in the absence of DNA damage, functioning as a molecular off-switch for the FA pathway.	PMID:31167143	Cell reports
2019	High	FANCL allosterically activates UBE2T via rewiring its intraresidue network to influence the active site, enabling site-specific FANCD2 monoubiquitination; a basic triad unique to UBE2T engages an acidic patch near the target lysine on FANCD2; this three-dimensional E2-substrate complementarity induced by FANCL is central to site-specific FA pathway ubiquitination.	PMID:31873223	Nature chemical biology
2020	High	ATR directly phosphorylates FANCI on S556, S559, and S565 to stabilize its association with DNA and FANCD2; this increased association stimulates ubiquitin conjugation to both FANCI and FANCD2 but also inhibits USP1-UAF1-mediated deubiquitination; S559 and S565 are particularly important for protecting the complex from deubiquitination.	PMID:32117957	Frontiers in cell and developmental biology
2020	High	Ubiquitination of FANCD2 promotes a conformational change in the ID2 complex that increases affinity for dsDNA via formation of a secondary 'Arm' ID2 interface that encircles DNA; ubiquitination of FANCI protects ubiquitin on FANCD2 from USP1-UAF1 deubiquitination via hydrophobic residues of FANCI's ubiquitin.	PMID:32510829	EMBO reports
2021	High	Crystal structures of USP1-UAF1 and cryo-EM reconstruction of USP1-UAF1 bound to monoubiquitinated FANCI-FANCD2 reveal that UAF1 makes an extensive interface with FANCI (confirmed by mutagenesis) driving conformational changes in the substrate; the N-terminus of USP1 harbors a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2 but not required for PCNA or FANCI deubiquitination.	PMID:33795880	Nature structural & molecular biology
2022	High	ATR-mediated phosphomimetic substitutions in FANCI cause FANCD2-FANCI to close around DNA independently of the FA core complex; phosphomimetic mutations destabilize the open state and alter conformational dynamics without substantially altering DNA binding affinity, demonstrating that phosphorylation primes the clamp for ubiquitination.	PMID:36050501	Nature structural & molecular biology
2023	High	Purified FANCD2 N-terminal domain directly binds and inhibits DNA2 nuclease activity; independently of FANCI dimerization, FANCD2 stabilizes RAD51 filaments to inhibit DNA2, MRE11, and EXO1; FANCD2-stabilized RAD51 filaments stimulate RAD51 strand exchange activity, revealing FANCD2 as a RAD51 mediator.	PMID:37526271	Nucleic acids research
2024	High	FANCD2-FANCI is a sliding clamp that diffuses on dsDNA; it stalls specifically at ssDNA-dsDNA junctions (structures present at stalled replication forks); cryo-EM structures show stalled D2-I makes distinct interactions with ss-dsDNA junctions compared to sliding D2-I, providing a unified mechanism for how D2-I surveys DNA and identifies stalled fork structures.	PMID:39085614	Nature
2024	Medium	SRSF1 physically interacts with FANCD2 and together they suppress R-loop formation via mRNA export regulation; SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion; FANCD2 monoubiquitination is required for assembly of the SRSF1-NXF1 nuclear export complex; cancer-associated SRSF1 mutants fail to interact with FANCD2, leading to impaired monoubiquitination, decreased mRNA export, and R-loop accumulation.	PMID:38165804	Cell reports

Citations

PMID:11239453
PMID:12239151
PMID:12447395
PMID:12874027
PMID:12887909
PMID:15115758
PMID:15314022
PMID:15454491
PMID:15601828
PMID:16860002
PMID:16943440
PMID:17352736
PMID:17412408
PMID:17420278
PMID:17938197
PMID:18082605
PMID:18212739
PMID:19561358
PMID:19609304
PMID:19633289
PMID:20603015
PMID:21355096
PMID:21764741
PMID:22287633
PMID:22855611
PMID:23538752
PMID:23806336
PMID:23993743
PMID:24556218
PMID:24623813
PMID:24726325
PMID:24794430
PMID:24794434
PMID:24905007
PMID:25659033
PMID:25801034
PMID:26797144
PMID:27264184
PMID:27405460
PMID:27427384
PMID:27694619
PMID:27768874
PMID:28196964
PMID:28378742
PMID:28687786
PMID:29030393
PMID:29394375
PMID:30431240
PMID:30650351
PMID:31167143
PMID:31253762
PMID:31873223
PMID:32066963
PMID:32117957
PMID:32510829
PMID:33795880
PMID:36050501
PMID:37526271
PMID:38165804
PMID:39085614

📚 Additional Documentation

Notes

(FANCD2-notes.md)

FANCD2 (Q9BXW9) review notes

Summary of biology

FANCD2 (Fanconi anemia group D2 protein; 1451 aa) is the central effector of the Fanconi
anemia (FA)/BRCA DNA interstrand crosslink (ICL) repair pathway. With its paralog FANCI it
forms the ID2 heterodimer. Upon replication stress/ICLs, FANCD2 is monoubiquitinated at
Lys561 by the FA core complex (E3 = FANCL, E2 = UBE2T), which converts the open ID2 trough
into a closed sliding DNA clamp that encircles duplex DNA, loading ID2 onto chromatin to
coordinate nucleolytic incision (unhooking), translesion synthesis (POLN) and homologous
recombination. It is deubiquitinated by the USP1–UAF1(WDR48) complex. FANCD2 also protects
stalled replication forks, restrains nucleases, and localizes to common fragile sites /
ultrafine anaphase bridges (with BLM). Loss causes Fanconi anemia complementation group D2:
bone marrow failure, congenital malformations, chromosomal instability, MMC/DEB
hypersensitivity, cancer predisposition.

Key provenance (verbatim)

ID2 clamp / monoubiquitination function:
PMID:32269332
PMID:32269332
PMID:32269332
Replication-coupled ICL repair, incision + TLS:
PMID:19965384
ssDNA binding / ring-like particle:
PMID:19609304
PMID:19609304
FANCI as monoubiquitinated paralog / partner:
PMID:17460694
BRCA2 direct interaction (HR):
PMID:15115758
PMID:18212739
FAN1 nuclease recruitment by monoubiquitinated FANCD2:
PMID:20603015
POLN interaction (crosslink repair / HR):
PMID:19995904
UHRF1/UHRF2 promote FANCD2 recruitment/monoubiquitination (nucleus/chromatin):
PMID:30335751
PMID:30335751
MEN1/menin interaction; enhanced by gamma-irradiation:
PMID:12874027
CEBPD/IPO4 nuclear import:
PMID:20805509
Monoubiquitination at Lys561 by FANCL/UBE2T; DUB USP1; chromatin binding requirement
(UniProt Q9BXW9 PTM/SUBUNIT sections).

Curation decisions (high level)

Core: interstrand cross-link repair (GO:0036297); ssDNA/damaged DNA binding (clamp);
DNA-repair (ID2) complex; nuclear/chromatin localization; HR-mediated DSB repair.
protein binding (GO:0005515, 11 IPI rows): REMOVE — uninformative MF; the underlying
interactions (FANCI, BRCA2, MEN1, MRE11/NBS1, FAN1, CEBPD, EGFR) are recorded here/in
more specific terms.
DNA polymerase binding (GO:0070182, IBA + POLN IPI): KEEP_AS_NON_CORE — real but peripheral.
Meiotic terms (GO:0007129, GO:1990918): KEEP_AS_NON_CORE (germline-restricted, IBA).
nucleolus (GO:0005730), response to gamma radiation (GO:0010332): KEEP_AS_NON_CORE.
Added NEW GO:0003697 single-stranded DNA binding (IDA, PMID:19609304).

📄 View Raw YAML

id: Q9BXW9
gene_symbol: FANCD2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FANCD2 is the central effector of the Fanconi anemia (FA)/BRCA pathway of replication-coupled
  DNA interstrand crosslink (ICL) repair. Together with its structural paralog FANCI it forms the
  ID2 heterodimer, which binds DNA with preference for branched structures. When a replication fork
  stalls at an ICL, FANCD2 is monoubiquitinated on Lys561 by the FA core complex (E3 ligase FANCL
  with the E2 UBE2T), an event that remodels the open ID2 trough into a closed sliding clamp that
  encircles duplex DNA and loads the complex onto chromatin. This activated ID2 clamp coordinates
  the downstream repair reactions: nucleolytic incision (unhooking) of the crosslink, translesion
  DNA synthesis past the lesion (e.g. via POLN), and homologous recombination, including recruitment
  of the structure-specific nuclease FAN1 and cooperation with BRCA2/FANCD1. FANCD2 is
  deubiquitinated by the USP1-UAF1(WDR48) complex once repair is complete. Beyond ICL repair, FANCD2
  protects and restarts stalled replication forks, suppresses breakage at common fragile sites, and
  localizes with BLM to ultrafine anaphase bridges to prevent chromosome missegregation. It is
  predominantly nuclear, concentrating in damage-induced foci during S phase. Biallelic loss-of-function
  causes Fanconi anemia complementation group D2, characterized by bone marrow failure, congenital
  malformations, chromosomal instability, hypersensitivity to crosslinking agents, and cancer
  predisposition.
alternative_products:
- name: '2'
  id: Q9BXW9-2
- name: '1'
  id: Q9BXW9-1
  sequence_note: VSP_057198
- name: '3'
  id: Q9BXW9-3
  sequence_note: VSP_013885, VSP_013886
- name: '4'
  id: Q9BXW9-4
  sequence_note: VSP_013883, VSP_013884
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: FANCD2 is a predominantly nuclear protein that concentrates in nuclear foci during S phase and genotoxic stress; the phylogenetic (IBA) nuclear localization is well supported.
    action: ACCEPT
    reason: Nuclear localization is firmly established experimentally and by UniProt subcellular location, and is consistent with FANCD2's chromatin-associated DNA repair function.
- term:
    id: GO:0007129
    label: homologous chromosome pairing at meiosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: A meiotic role (promoting accurate pairing of homologs) is inferred phylogenetically and supported by high FANCD2 expression in maturing spermatocytes and fetal oocytes, but this is a germline-restricted, non-core activity relative to the somatic ICL-repair function.
    action: KEEP_AS_NON_CORE
    reason: Meiotic pairing is a genuine but tissue-restricted function derived from model-organism orthologs; it is peripheral to the central FA-pathway ICL-repair role in somatic cells.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Highly expressed in testis, where expression is restricted to maturing spermatocytes.
- term:
    id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: FANCD2 participates in the S-phase (intra-S) DNA damage checkpoint; ATM phosphorylation of Ser222 is required for checkpoint activation, and the ATR-NBS1-FANCD2 axis mediates the crosslink-induced S-phase checkpoint.
    action: ACCEPT
    reason: The intra-S checkpoint function is documented experimentally and is an integral part of FANCD2's replication-stress response, consistent with the phylogenetic annotation.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Phosphorylation on Ser-222 is required for S-phase checkpoint activation, but not for ubiquitination, foci formation, or DNA repair
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Interstrand crosslink repair is the defining, core biological process of FANCD2; the monoubiquitinated FANCI-FANCD2 complex is required for replication-coupled ICL repair.
    action: ACCEPT
    reason: This is the central, best-supported function of FANCD2 and is correctly annotated at the appropriate level of specificity.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
- term:
    id: GO:1990918
    label: double-strand break repair involved in meiotic recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: A meiotic double-strand-break-repair role is inferred phylogenetically. FANCD2 clearly participates in somatic DSB repair by homologous recombination, but the specifically meiotic recombination context is germline-restricted and non-core.
    action: KEEP_AS_NON_CORE
    reason: The general DSB/HR repair activity is core, but the meiotic-recombination-specific term is a tissue-restricted specialization derived from orthologs; retain as non-core.
- term:
    id: GO:0000793
    label: condensed chromosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: FANCD2 localizes to condensed mitotic chromosomes, appearing as paired foci on sister-chromatid arms at common fragile sites and at ultrafine anaphase bridges.
    action: ACCEPT
    reason: Mitotic-chromosome localization is experimentally documented and consistent with FANCD2's role in protecting missegregating chromatin after replication stress.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Observed in a few spots localized in pairs on the sister chromatids of mitotic chromosome arms and not centromeres
- term:
    id: GO:0070182
    label: DNA polymerase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: FANCD2 physically and functionally interacts with the translesion/HR polymerase POLN; DNA polymerase binding is a real but peripheral molecular activity relative to the core DNA-binding clamp scaffold function.
    action: KEEP_AS_NON_CORE
    reason: The interaction with POLN is genuine and more informative than generic protein binding, but it is an accessory activity supporting downstream translesion synthesis rather than FANCD2's core function.
    supported_by:
    - reference_id: PMID:19995904
      supporting_text: we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic mapping from the UniProt subcellular-location vocabulary places FANCD2 in the nucleus, consistent with all experimental evidence.
    action: ACCEPT
    reason: Nuclear localization is well established; the IEA mapping is correct.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-to-GO electronic annotation places FANCD2 in the broad DNA repair process; this parent term is correct though less specific than interstrand cross-link repair.
    action: ACCEPT
    reason: DNA repair is a correct, appropriately conservative parent term for FANCD2; the more specific child term (ICL repair) is also annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12874027
  qualifier: enables
  review:
    summary: This IPI records the FANCD2-MEN1 (menin) interaction. Protein binding is an uninformative molecular-function term; the interaction is captured in the notes and does not define a specific FANCD2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic for curation. The menin interaction (enhanced by gamma-irradiation) is real but does not correspond to a defined FANCD2 molecular function.
    supported_by:
    - reference_id: PMID:12874027
      supporting_text: menin specifically interacts with FANCD2, a protein encoded by a gene involved in DNA repair
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15115758
  qualifier: enables
  review:
    summary: This IPI records the direct FANCD2-BRCA2 interaction that links FANCD2 to homologous recombination. The interaction is biologically important but protein binding is an uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic. The BRCA2 interaction is retained as evidence for FANCD2's role in HR-mediated repair (captured in core functions/notes) rather than as a generic binding annotation.
    supported_by:
    - reference_id: PMID:15115758
      supporting_text: FANCD2 and BRCA2 can be coimmunoprecipitated from cell extracts of both human and Chinese hamster wild-type cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17460694
  qualifier: enables
  review:
    summary: This IPI records the interaction with FANCI, FANCD2's obligate partner in the ID2 complex. Although central to FANCD2 biology, protein binding is uninformative as an MF and the ID2 complex membership is annotated separately.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic. FANCI partnership is captured by the DNA repair (ID2) complex annotation and core functions, not by a generic binding term.
    supported_by:
    - reference_id: PMID:17460694
      supporting_text: the discovery of FANCI, a second monoubiquitinated component of the FA pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18212739
  qualifier: enables
  review:
    summary: This IPI records the FANCD2-BRCA2 interaction within a FANCG/XRCC3-containing complex. Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic; the FANCG-dependent BRCA2-FANCD2-XRCC3 complex is relevant to HR but does not define a specific FANCD2 molecular function.
    supported_by:
    - reference_id: PMID:18212739
      supporting_text: phosphorylation of FANCG serine 7 is required for its co-precipitation with BRCA2, XRCC3 and FANCD2, as well as the direct interaction of BRCA2-FANCD2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19609304
  qualifier: enables
  review:
    summary: This IPI records interaction with the MRE11-RAD50-NBS1 (MRN) complex, which regulates FANCD2 stability and function at DSBs. Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic. The MRN relationship is captured as a regulatory interaction in the notes; it does not correspond to a defined FANCD2 molecular activity.
    supported_by:
    - reference_id: PMID:19609304
      supporting_text: Our data establish MRN as a crucial regulator of FANCD2 stability and function in the DNA damage response.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20603015
  qualifier: enables
  review:
    summary: This IPI records interactions from the FAN1 discovery study (including FAN1/MTMR15 recruited by monoubiquitinated FANCD2). Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic. FAN1 recruitment by monoubiquitinated FANCD2 is a key mechanistic finding but is best represented through process/complex annotations rather than generic binding.
    supported_by:
    - reference_id: PMID:20603015
      supporting_text: KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20805509
  qualifier: enables
  review:
    summary: This IPI records the FANCD2-CEBPD interaction that, via IPO4, promotes nuclear import and monoubiquitination of FANCD2. Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic; the CEBPD/IPO4 interaction is an upstream regulatory step for FANCD2 activation, not a FANCD2 molecular function.
    supported_by:
    - reference_id: PMID:20805509
      supporting_text: augmenting nuclear import of FANCD2, a prerequisite for its monoubiquitination
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35384245
  qualifier: enables
  review:
    summary: This IPI derives from a high-throughput receptor tyrosine kinase interactome atlas reporting an EGFR interaction. Protein binding is uninformative and this proteome-scale interaction has no established FANCD2 functional context.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic and this high-throughput EGFR interaction is not connected to any characterized FANCD2 molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    summary: This IPI derives from a systematic screen for mutation-directed neo-protein-protein interactions in cancer (EGFR). Protein binding is uninformative and lacks established FANCD2 functional relevance.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic; the reported neo-interaction has no characterized bearing on FANCD2's core biology.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: located_in
  review:
    summary: FANCD2 associates with chromatin in a monoubiquitination-dependent manner; chromatin retention is required for its DNA-repair function.
    action: ACCEPT
    reason: Chromatin localization is well established and mechanistically central (ubiquitination is required for chromatin binding); the ComplexPortal NAS annotation is appropriate.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Ubiquitination is required for binding to chromatin, interaction with BRCA1, BRCA2 and MTMR15/FAN1, DNA repair, and normal cell cycle progression
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: NAS
  original_reference_id: PMID:19965384
  qualifier: involved_in
  review:
    summary: ICL repair is FANCD2's core biological process; the FANCI-FANCD2 complex is required for replication-coupled ICL repair, with FANCD2 removal blocking both incision and translesion synthesis.
    action: ACCEPT
    reason: Correct, well-supported core-process annotation; consistent with the IBA annotation of the same term.
    supported_by:
    - reference_id: PMID:19965384
      supporting_text: Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion.
- term:
    id: GO:1990391
    label: DNA repair complex
  evidence_type: IPI
  original_reference_id: PMID:32269332
  qualifier: part_of
  review:
    summary: FANCD2 is a subunit of the FANCI-FANCD2 (ID2) DNA-repair complex; the monoubiquitinated ID2 complex forms a closed ring that encircles DNA and acts as a sliding clamp.
    action: ACCEPT
    reason: Membership in the ID2 DNA-repair complex is central to FANCD2 function and is directly supported by cryo-EM structural work.
    supported_by:
    - reference_id: PMID:32269332
      supporting_text: The ID complex, involving the proteins FANCI and FANCD2, is required for the repair of DNA interstrand crosslinks (ICL) and related lesions
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) localizes FANCD2 to the nucleoplasm, consistent with its diffuse nuclear distribution outside of damage-induced foci.
    action: ACCEPT
    reason: Nucleoplasmic localization is consistent with established nuclear localization and the numerous concordant annotations.
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence reports FANCD2 in the nucleolus. A nucleolar pool has been described, but this is a minor/context-dependent localization relative to the nucleoplasmic and chromatin pools that carry out ICL repair.
    action: KEEP_AS_NON_CORE
    reason: Nucleolar localization is plausible but peripheral to FANCD2's core chromatin-associated DNA-repair function; retain as non-core.
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: FANCD2 concentrates into damage-induced nuclear foci (nuclear bodies) during S phase and after genotoxic stress, a hallmark of its activation.
    action: ACCEPT
    reason: Nuclear-focus (nuclear body) localization is a well-documented, functionally meaningful feature of activated FANCD2.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Concentrates in nuclear foci during S phase and upon genotoxic stress
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:30335751
  qualifier: located_in
  review:
    summary: FANCD2 is recruited to and retained on chromatin at ICLs in the nucleus, cooperating with UHRF1/UHRF2 for its activation.
    action: ACCEPT
    reason: Experimental evidence supports nuclear/chromatin localization; consistent with all other nuclear annotations.
    supported_by:
    - reference_id: PMID:30335751
      supporting_text: The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Reactome places FANCD2 in the nucleoplasm within the FANCD2-FANCI/UBE2T ICL-DNA binding step of the FA pathway.
    action: ACCEPT
    reason: Author-stated nucleoplasmic localization consistent with FANCD2 nuclear biology and the FA pathway reaction context.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the monoubiquitination-of-FANCD2/FANCI reaction.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization during FA-pathway activation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785594
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the FANCD2-binds-FANCI reaction.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for DNA nucleases binding the monoubiquitinated ID2 complex.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization within the ICL-repair reaction context.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the nuclease-mediated unhooking of the ICL step.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the POLN-binds-ICL-DNA step of the FA pathway.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the POLN translesion-synthesis step.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the FANCD2 deubiquitination by USP1/WDR48 step.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the ATR/ATRIP recruitment to ICL-DNA step.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization for the ATR phosphorylation of RPA2/FANCI/FANCD2/FANCM step.
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6797712
  qualifier: located_in
  review:
    summary: Reactome nucleoplasmic localization associated with CDK12 stimulation of DNA repair gene expression (FA pathway context).
    action: ACCEPT
    reason: Consistent with FANCD2's established nucleoplasmic localization.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26323318
  qualifier: located_in
  review:
    summary: Direct-assay nuclear localization of FANCD2, consistent with all other evidence for a nuclear protein.
    action: ACCEPT
    reason: Nuclear localization is firmly established; the IDA annotation is correct.
    supported_by:
    - reference_id: PMID:26323318
      supporting_text: the levels of soluble nuclear and chromatin-associated ATM, FANCD2
- term:
    id: GO:0070182
    label: DNA polymerase binding
  evidence_type: IPI
  original_reference_id: PMID:19995904
  qualifier: enables
  review:
    summary: FANCD2 interacts with the DNA polymerase POLN, which participates in crosslink repair and homologous recombination downstream of FA-pathway activation. This is a genuine but peripheral molecular activity.
    action: KEEP_AS_NON_CORE
    reason: DNA polymerase (POLN) binding is more informative than generic protein binding and is experimentally supported, but represents an accessory interaction rather than FANCD2's core DNA-binding clamp function; consistent with the IBA annotation of the same term.
    supported_by:
    - reference_id: PMID:19995904
      supporting_text: we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20603016
  qualifier: enables
  review:
    summary: This IPI records a FAN1-related interaction from a study showing FAN1 deficiency sensitizes cells to crosslinking agents. Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic. The FAN1 relationship is captured through FANCD2's ICL-repair process annotations rather than a generic binding term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20603073
  qualifier: enables
  review:
    summary: This IPI records a FAN1-related interaction from a genetic screen identifying FAN1 as an FA-associated nuclease. Protein binding is uninformative as an MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is too generic; the FAN1 nuclease relationship is represented through process/complex annotations, not a generic binding term.
- term:
    id: GO:0010332
    label: response to gamma radiation
  evidence_type: IDA
  original_reference_id: PMID:12874027
  qualifier: involved_in
  review:
    summary: FANCD2 responds to ionizing/gamma radiation (ATM-dependent Ser222/Ser1404 phosphorylation and foci formation); in this study the FANCD2-menin interaction was enhanced by gamma-irradiation.
    action: KEEP_AS_NON_CORE
    reason: Responsiveness to gamma radiation is a real facet of FANCD2's DNA-damage response but is a downstream/secondary aspect relative to its core replication-coupled ICL-repair function.
    supported_by:
    - reference_id: PMID:12874027
      supporting_text: The interaction between menin and FANCD2 is enhanced by gamma-irradiation.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19609304
  qualifier: enables
  review:
    summary: Purified FANCD2 is a ring-like particle that preferentially binds single-stranded DNA over other substrates, consistent with its DNA-binding scaffold/clamp role in repair. This molecular-function is missing from the current GOA set (which lists only generic protein binding and DNA polymerase binding).
    action: NEW
    reason: A defined DNA-binding molecular function is needed to represent FANCD2's core biochemical activity; direct in vitro evidence supports single-stranded DNA binding.
    supported_by:
    - reference_id: PMID:19609304
      supporting_text: Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: ISS
  original_reference_id: PMID:15601828
  qualifier: involved_in
  review:
    summary: >-
      FANCD2 promotes homologous-recombination repair of DNA double-strand breaks; the FA
      monoubiquitination pathway is required for efficient HR, and FANCD2 loads BRCA2/FANCD1
      onto damaged chromatin. The direct loss-of-function evidence quoted below is from a
      CHICKEN DT40 fancd2 line, not from human cells. This core HR-repair process is not
      explicitly captured by the existing GOA terms.
    action: NEW
    reason: >-
      FANCD2's role in double-strand break repair by homologous recombination is well
      documented and is a core process underlying its ICL-repair and genome-stability
      functions, but the primary loss-of-function experiment is in chicken DT40 cells, so the
      code is ISS rather than IMP - an IMP would assert a human mutant phenotype that this
      reference does not provide. original_reference_id changed from the derived
      FANCD2-uniprot.txt to the primary paper, since a UniProt flat file is not a valid basis
      for an author-supplied experimental-evidence annotation.
    supported_by:
    - reference_id: file:human/FANCD2/FANCD2-uniprot.txt
      supporting_text: Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing
    - reference_id: PMID:15601828
      supporting_text: FANCD2-disrupted DT40 chicken B-cell line is defective in HR-mediated DNA double-strand break (DSB) repair, as well as gene conversion at the immunoglobulin light-chain locus
- term:
    id: GO:0031297
    label: replication fork processing
  evidence_type: IMP
  original_reference_id: PMID:25659033
  qualifier: involved_in
  review:
    summary: Beyond ICL repair, FANCD2 protects and promotes recovery of stalled replication forks. Non-ubiquitinated FANCD2 acts with the BLM helicase complex to restart aphidicolin-stalled forks while suppressing new origin firing, and monoubiquitinated FANCD2 recruits the FAN1 nuclease to restrain fork progression and prevent chromosome abnormalities even in the absence of crosslinks. This core genome-maintenance activity is described in the review narrative but is not otherwise captured by a GOA term.
    action: NEW
    reason: Replication fork protection/restart is a well-documented FANCD2 function, distinct from and partly independent of the canonical monoubiquitination/ICL-repair role; GO:0031297 (replication fork processing, restoration and restart of stalled forks) is the appropriate specific process term.
    supported_by:
    - reference_id: PMID:25659033
      supporting_text: it binds chromatin and acts in concert with the BLM helicase complex to promote the restart of aphidicolin (APH)-stalled replication forks, while suppressing the firing of new replication origins
    - reference_id: PMID:26797144
      supporting_text: restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs
- term:
    id: GO:0062176
    label: R-loop processing
  evidence_type: IMP
  original_reference_id: PMID:30431240
  qualifier: involved_in
  review:
    summary: FANCD2 suppresses R-loop (RNA-DNA hybrid) accumulation during replication stress by recruiting RNA-processing factors (hnRNP U, DDX47) to R-loop-containing chromatin and, with SRSF1, promoting mRNA export; this reduces transcription-replication collisions and preserves genome stability. This genome-protective activity is not represented in the current GOA set.
    action: NEW
    reason: R-loop suppression is a genuine, experimentally supported secondary function of FANCD2 (independent studies converge on it); GO:0062176 (R-loop processing, disassembly/resolution of R-loops) is the correctly branched process term. Non-core relative to ICL repair but well evidenced.
    supported_by:
    - reference_id: PMID:30431240
      supporting_text: we found that FANCD2 suppresses R-loop levels. Furthermore, we identified FANCD2 interactions with RNA processing factors, including hnRNP U and DDX47
    - reference_id: PMID:38165804
      supporting_text: Defects in the FA pathway lead to R-loop accumulation, which contributes to genomic instability
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISO
  original_reference_id: PMID:28378742
  qualifier: located_in
  review:
    summary: >-
      A mitochondrial pool of Fancd2 has been reported IN MOUSE, in which Fancd2 localizes to
      mitochondria and associates with the nucleoid components Atad3 and Tufm, whose complex is
      disrupted in Fancd2-/- cells, implicating Fancd2 in a non-canonical mitochondrial
      homeostasis role. PMID:28378742 is a mouse-only study (Fancd2 3xFLAG/HA knock-in mouse,
      MEFs and mouse organs); there is no human observation of this pool, so the human
      annotation is by orthology only. Peripheral to the nuclear DNA-repair function.
    action: NEW
    reason: >-
      Mitochondrial localization is experimentally documented, but only for the mouse ortholog,
      so the evidence code is ISO (with UniProtKB:Q80V54, mouse Fancd2) rather than IDA - an IDA
      here would assert a direct human observation that does not exist. Non-canonical and
      non-core relative to FANCD2's central nuclear ICL-repair function; added as a secondary
      localization for completeness, explicitly flagged as mouse-derived.
    supported_by:
    - reference_id: PMID:28378742
      supporting_text: Fancd2 localizes in the mitochondrion and associates with the nucleoid complex components Atad3 and Tufm
core_functions:
- description: >-
    With its paralog FANCI, FANCD2 forms the ID2 DNA-repair complex that binds DNA and, upon
    FANCL/UBE2T-catalyzed monoubiquitination at Lys561, is remodeled into a closed sliding clamp
    encircling duplex DNA. FANCD2 itself preferentially binds single-stranded DNA. This
    chromatin-loaded, DNA-binding clamp scaffold coordinates the core steps of replication-coupled
    interstrand crosslink repair (nucleolytic incision, translesion synthesis) and homologous
    recombination, and recruits downstream factors such as the nuclease FAN1.
  molecular_function:
    id: GO:0003697
    label: single-stranded DNA binding
  directly_involved_in:
  - id: GO:0036297
    label: interstrand cross-link repair
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  - id: GO:0031297
    label: replication fork processing
  - id: GO:0031573
    label: mitotic intra-S DNA damage checkpoint signaling
  locations:
  - id: GO:0000785
    label: chromatin
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:1990391
    label: DNA repair complex
  supported_by:
  - reference_id: PMID:19609304
    supporting_text: Purified FANCD2, a ring-like particle by electron microscopy, preferentially bound ssDNA over various DNA substrates.
  - reference_id: PMID:32269332
    supporting_text: the monoubiquitinated ID complex loses its preference for ICL and related branched DNA structures, and becomes a sliding DNA clamp that can coordinate the subsequent repair reactions
  - reference_id: PMID:19965384
    supporting_text: FANCI-FANCD2 is required for replication-coupled ICL repair in S phase.
proposed_new_terms: []
suggested_questions:
- question: What is the minimal DNA substrate recognized by unmodified FANCD2 versus the monoubiquitinated ID2 clamp, and how does this specificity switch coordinate incision, translesion synthesis and HR in vivo?
- question: To what extent are the reported nucleolar and replication-fork-protection activities of FANCD2 separable from its canonical ID2 monoubiquitination function?
suggested_experiments:
- description: Separation-of-function alleles (Lys561 ubiquitination-dead and DNA-binding mutants) assayed for ICL incision, translesion synthesis, HR, and fork protection to map which activities require the sliding-clamp conformation.
- description: Genome-wide mapping (ChIP-seq or CUT-and-RUN) of chromatin-bound versus monoubiquitinated FANCD2 under replication stress to define its DNA-structure and locus preferences relative to common fragile sites.
references:
- id: file:human/FANCD2/FANCD2-uniprot.txt
  title: UniProtKB entry Q9BXW9 (FACD2_HUMAN), Fanconi anemia group D2 protein
  findings: []
- 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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:12874027
  title: Menin associates with FANCD2, a protein involved in repair of DNA damage.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. Reports FANCD2-menin interaction enhanced by gamma-irradiation; supports the gamma-radiation-response annotation but the interaction itself is peripheral to core function.
- id: PMID:15115758
  title: Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes direct FANCD2-BRCA2 interaction linking FANCD2 to homologous recombination; supports HR involvement.
- id: PMID:17460694
  title: FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Identifies FANCI, FANCD2's obligate ID2-complex partner and second monoubiquitinated FA component.
- id: PMID:18212739
  title: FANCG promotes formation of a newly identified protein complex containing
    BRCA2, FANCD2 and XRCC3.
  findings: []
- id: PMID:19609304
  title: MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability and function
    during DNA double-strand break repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Shows purified FANCD2 is a ring-like particle preferentially binding ssDNA; primary support for the single-stranded DNA binding core molecular function.
- id: PMID:19965384
  title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand
    cross-link repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Cell-free demonstration that FANCI-FANCD2 is required for replication-coupled ICL repair, controlling both incision and translesion synthesis.
- id: PMID:19995904
  title: DNA polymerase POLN participates in cross-link repair and homologous recombination.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Supports the FANCD2-POLN (DNA polymerase binding) interaction in the context of crosslink repair and HR.
- id: PMID:20603015
  title: Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage
    by monoubiquitinated FANCD2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. FAN1 nuclease is recruited to DNA damage by monoubiquitinated FANCD2, a key downstream effector step.
- id: PMID:20603016
  title: Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to
    interstrand crosslinking agents.
  findings: []
- id: PMID:20603073
  title: A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary
    for DNA interstrand crosslink repair.
  findings: []
- id: PMID:20805509
  title: CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear
    import of FANCD2 by IPO4 augments cellular response to DNA damage.
  findings: []
- id: PMID:26323318
  title: NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination
    and genome stability.
  findings: []
- id: PMID:30335751
  title: Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. UHRF1/UHRF2 ensure recruitment and chromatin retention of FANCD2 at ICLs, stimulating its monoubiquitination.
- id: PMID:32269332
  title: DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Cryo-EM structures showing monoubiquitination converts the ID2 complex into a sliding DNA clamp encircling DNA; defines the core mechanistic function.
- id: PMID:35384245
  title: Physical and functional interactome atlas of human receptor tyrosine kinases.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: PubMed-verified high-throughput RTK interactome atlas. The reported EGFR-FANCD2 interaction is proteome-scale with no established FANCD2 functional context; basis for removing the generic protein binding annotation.
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions
    in cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: PubMed-verified systematic neo-PPI screen. Reported EGFR interaction lacks characterized FANCD2 functional relevance; basis for removing the generic protein binding annotation.
- id: PMID:15601828
  title: Fanconi anemia protein FANCD2 promotes immunoglobulin gene conversion and
    DNA repair through a mechanism related to homologous recombination.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. FANCD2-null DT40 cells are defective in HR-mediated DSB repair and Ig gene conversion; primary experimental support for the FANCD2 role in homologous-recombination DSB repair.
- id: PMID:25659033
  title: FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently
    of the Fanconi Anemia core complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Non-ubiquitinated FANCD2 acts with the BLM complex to restart aphidicolin-stalled forks and suppress new origin firing, independently of the FA core complex; primary support for the replication fork processing annotation.
- id: PMID:26797144
  title: Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent
    genome instability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. Ub-FANCD2/FAN1 restrains replication fork progression and prevents chromosome abnormalities at stalled forks even without ICLs; supports the fork-protection (replication fork processing) function.
- id: PMID:30431240
  title: FANCD2 protects genome stability by recruiting RNA processing enzymes to
    resolve R-loops during mild replication stress.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. FANCD2 suppresses R-loop levels and recruits hnRNP U and DDX47 to R-loop chromatin during replication stress; primary support for the R-loop processing annotation.
- id: PMID:38165804
  title: The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through
    SRSF1-mediated mRNA export.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified. SRSF1-FANCD2 cooperation suppresses R-loops via mRNA export; corroborating support for the R-loop processing function and its link to genome stability.
- id: PMID:28378742
  title: Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial
    function.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified. In vivo interactome shows a mitochondrial FANCD2 pool associating with the ATAD3-TUFM nucleoid complex; supports the non-canonical mitochondrion localization annotation.
- id: Reactome:R-HSA-6785342
  title: FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex
  findings: []
- id: Reactome:R-HSA-6785361
  title: Monoubiquitination of FANCD2:FANCI
  findings: []
- id: Reactome:R-HSA-6785594
  title: FANCD2 binds FANCI
  findings: []
- id: Reactome:R-HSA-6785732
  title: DNA nucleases bind monoubiquitinated ID2 complex
  findings: []
- id: Reactome:R-HSA-6785986
  title: DNA nucleases unhook the interstrand crosslink (ICL)
  findings: []
- id: Reactome:R-HSA-6786155
  title: POLN binds ICL-DNA
  findings: []
- id: Reactome:R-HSA-6786166
  title: Translesion synthesis across unhooked ICL by POLN
  findings: []
- id: Reactome:R-HSA-6786171
  title: FANCD2 deubiquitination by USP1:WDR48
  findings: []
- id: Reactome:R-HSA-6788385
  title: The complex of ATR and ATRIP is recruited to ICL-DNA
  findings: []
- id: Reactome:R-HSA-6788392
  title: ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA
  findings: []
- id: Reactome:R-HSA-6797712
  title: CDK12 stimulates expression of DNA repair genes
  findings: []

FANCD2

Gene Description