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.
| 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 |
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Download this section (compressed HTML)Q: 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?
Q: To what extent are the reported nucleolar and replication-fork-protection activities of FANCD2 separable from its canonical ID2 monoubiquitination function?
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.
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