id: Q8IYD8
gene_symbol: FANCM
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FANCM is a large (~250 kDa) DEAH-box family DNA-dependent ATPase and ATP-dependent DNA
  translocase that acts at stalled replication forks and DNA interstrand crosslinks (ICLs) to
  maintain genome stability. It is the most conserved Fanconi anemia protein, orthologous to
  archaeal Hef and to yeast Mph1/Fml1. Its N-terminal SF2 helicase/translocase domain (Walker A
  ATP-binding site, catalytic Lys117) uses ATP hydrolysis to translocate on duplex DNA and to
  catalyze branch migration of replication forks and Holliday junctions, thereby remodeling
  branched replication/recombination intermediates. Its catalytically dead C-terminal ERCC4/XPF-like
  domain heterodimerizes with FAAP24, and a central region binds the MHF1-MHF2 histone-fold dimer
  (CENPS-CENPX); the MHF dimer stimulates FANCM DNA binding and fork remodeling. Through these
  interactions FANCM anchors the Fanconi anemia core complex to chromatin at sites of replication
  stress, which is required for efficient DNA damage-induced monoubiquitination of the FANCD2-FANCI
  complex and for ATR checkpoint signaling. FANCM also promotes replication traverse of ICLs and
  suppresses sister-chromatid exchange and crossover recombination, acting as a regulator of
  homologous recombination rather than a core HR enzyme. The protein is nuclear and chromatin-bound,
  becomes hyperphosphorylated in response to genotoxic stress, and is highly expressed in germ
  cells; biallelic loss-of-function causes spermatogenic failure and premature ovarian failure.
alternative_products:
- name: '1'
  id: Q8IYD8-1
- name: '2'
  id: Q8IYD8-2
  sequence_note: VSP_015989, VSP_015990
- name: '3'
  id: Q8IYD8-3
  sequence_note: VSP_054504
existing_annotations:
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      FANCM functions in interstrand cross-link (ICL) repair; it is recruited to forks stalled by
      ICLs and is required for cellular resistance to cross-linking agents. This is a core biological
      process for FANCM, consistent across the phylogenetic tree (Hef/Mph1/Fml1).
    action: ACCEPT
    reason: >-
      Well supported by both the phylogenetic inference and direct human experiments; ICL repair is
      a defining FANCM function.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: FANCM and MHF are rapidly recruited to forks stalled by DNA interstrand crosslinks, and both are required for cellular resistance to such lesions.
- term:
    id: GO:0000400
    label: four-way junction DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      FANCM binds branched DNA including Holliday (four-way) junctions, which it processes by branch
      migration. Binding to four-way junction DNA is a conserved biochemical property.
    action: ACCEPT
    reason: >-
      Supported by biochemistry showing FANCM processes Holliday junctions by branch migration, which
      requires four-way junction binding.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM translocates on dsDNA and can unwind the D-loop and also process branched DNA structures, such as model DNA replication forks and the Holliday junction, by DNA branch migration
    - reference_id: PMID:18206976
      supporting_text: purified FANCM binds to Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner
- term:
    id: GO:0009378
    label: four-way junction helicase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      FANCM catalyzes ATP-dependent branch migration of Holliday (four-way) junctions, the activity
      captured by this term (Holliday junction branch migration/helicase activity), conserved from
      yeast Mph1/Fml1.
    action: ACCEPT
    reason: >-
      FANCM demonstrably processes Holliday junctions by ATP-dependent branch migration; this term is
      an accurate description of that activity.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM translocates on dsDNA and can unwind the D-loop and also process branched DNA structures, such as model DNA replication forks and the Holliday junction, by DNA branch migration
    - reference_id: PMID:18206976
      supporting_text: FANCM can dissociate large recombination intermediates, via branch migration of Holliday junctions through 2.6 kb of DNA
- term:
    id: GO:0043138
    label: 3'-5' DNA helicase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Human FANCM does not display canonical processive 3'-5' duplex-unwinding helicase activity; the
      characterized enzymatic activity is ATP-dependent DNA translocation and branch migration of
      branched substrates. The 3'-5' DNA helicase term (propagated from the SF2 family) is more
      accurately expressed as DNA translocase activity.
    action: MODIFY
    reason: >-
      Direct biochemistry states that for FANCM only translocase (not helicase) activity was observed;
      the branch-migration/fork-remodeling activity is best described as DNA translocase activity
      rather than a duplex-unwinding 3'-5' helicase.
    proposed_replacement_terms:
    - id: GO:0015616
      label: DNA translocase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: PANTHER:PTN000361481
        source_label: FANCM/Mph1/Fml1 family node
      - source_id: SGD:S000001441
        source_label: MPH1
      - source_id: PomBase:SPAC9.05
        source_label: fml1
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: for FANCM only translocase activity was observed
- term:
    id: GO:0045003
    label: double-strand break repair via synthesis-dependent strand annealing
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Yeast orthologs (Mph1/Fml1) promote synthesis-dependent strand annealing / gene conversion at
      blocked forks and channel recombination toward non-crossover outcomes. Human FANCM has a
      regulatory rather than essential role in this HR sub-pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      SDSA is a conserved role of the FANCM clade but is regulatory/context-specific for human FANCM,
      which is not essential for RAD51-dependent HR; retain as a non-core process.
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: FANCM may have a more regulatory function in the homologous recombination process
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Broad InterPro-based binding term. FANCM binds DNA (more specific terms DNA binding and
      chromatin binding are separately annotated).
    action: ACCEPT
    reason: >-
      Correct but general IEA parent of the more informative DNA-binding annotations; acceptable as a
      broad electronic annotation.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      FANCM binds DNA, including single-stranded, fork-structured and branched substrates (and, with
      FAAP24/MHF, additional structures). Well supported.
    action: ACCEPT
    reason: DNA binding is directly demonstrated and central to FANCM function.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM translocates on dsDNA and can unwind the D-loop and also process branched DNA structures, such as model DNA replication forks and the Holliday junction, by DNA branch migration
- term:
    id: GO:0003724
    label: RNA helicase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: >-
      This annotation derives from an EC:3.6.4.13 -> GO mapping and the legacy alternative name
      "ATP-dependent RNA helicase FANCM". Functionally FANCM is a DNA-dependent ATPase / DNA
      translocase; no RNA helicase activity has been demonstrated. Its measured catalytic reaction is
      simply ATP hydrolysis, and its substrates are DNA structures.
    action: REMOVE
    reason: >-
      Demonstrably incorrect EC-based electronic mapping: FANCM acts on DNA (translocase/branch
      migration), not RNA. The EC 3.6.4.13 assignment reflects ATP hydrolase activity, not genuine
      RNA helicase function.
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: for FANCM only translocase activity was observed
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      FANCM contains a Walker A/DEAH ATP-binding motif (residues 111-118, catalytic Lys117) and binds
      ATP, which it hydrolyzes to power DNA translocation.
    action: ACCEPT
    reason: Directly supported by the conserved ATP-binding motif and ATPase mutagenesis (K117R).
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: FANCM is a nuclear protein. Well supported by multiple experimental studies.
    action: ACCEPT
    reason: Consistent nuclear localization across studies.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      FANCM functions broadly in DNA repair (ICL repair, replication fork protection, FA pathway
      activation). Correct general BP annotation.
    action: ACCEPT
    reason: Accurate broad process term supported by the entire FANCM literature.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      FANCM is a DNA-dependent ATPase; ATP hydrolysis powers its translocase/branch-migration
      activity. Matches EC 3.6.4.13 (ATP + H2O -> ADP + Pi).
    action: ACCEPT
    reason: Directly demonstrated DNA-stimulated ATPase activity; consistent with Rhea mapping.
- term:
    id: GO:0035825
    label: homologous recombination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      FANCM regulates homologous recombination (D-loop disruption, fork reversal, suppression of
      crossovers/sister-chromatid exchange) but is not essential for RAD51-dependent HR repair itself.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine but regulatory HR role; patient cells with FANCM loss retain normal RAD51 foci,
      indicating FANCM is not a core HR enzyme. Retain as non-core.
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: normal Rad51 foci, indicating that FANCM is not essential for homologous recombination repair
- term:
    id: GO:0043138
    label: 3'-5' DNA helicase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Duplicate of the IBA 3'-5' DNA helicase annotation, here from InterPro. As above, human FANCM's
      catalytic activity is ATP-dependent DNA translocation/branch migration rather than a processive
      duplex-unwinding helicase.
    action: MODIFY
    reason: >-
      Same rationale as the IBA entry: the SF2-family helicase mapping over-specifies FANCM's activity;
      DNA translocase activity is the accurate molecular function.
    proposed_replacement_terms:
    - id: GO:0015616
      label: DNA translocase activity
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: for FANCM only translocase activity was observed
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17289582
  qualifier: enables
  review:
    summary: >-
      IPI capturing the FANCM-FAAP24 interaction. FAAP24 binds the C-terminal ERCC4-like region of
      FANCM and targets it to damaged-DNA structures. The interaction is biologically meaningful but
      the generic "protein binding" term is uninformative and is captured functionally by the FA
      core/complex annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) is uninformative as a molecular function; the specific
      FANCM-FAAP24 interaction is represented via complex-membership terms.
    supported_by:
    - reference_id: PMID:17289582
      supporting_text: associates with the C-terminal region of FANCM, and is a component of the FA core complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome mapping (interaction reported with TRIM27). Generic protein-binding
      annotation with no specific functional content.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative "protein binding" term from a proteome-scale interactome screen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary interactome map (interaction reported with EPN2 isoform). Generic
      protein-binding annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative "protein binding" term from a large-scale interactome dataset.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32769987
  qualifier: enables
  review:
    summary: >-
      Interaction with MCM2 reported in a replisome study; FANCM associates with a subset of
      replisomes in late-replicating heterochromatin. The generic protein-binding term does not
      convey this.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative "protein binding" molecular-function term; replisome association is a process/localization observation, not a molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome (FAAP24 interaction). Duplicative generic protein-binding
      annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative "protein binding" term; the FANCM-FAAP24 relationship is captured by complex-membership annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      Multimodal cell-map interactome (FAAP24 interaction). Generic protein-binding annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative "protein binding" term from a proteome-scale mapping effort.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based nucleoplasm localization (HPA). Consistent with FANCM being a nuclear,
      chromatin-associated protein.
    action: ACCEPT
    reason: Consistent with the nuclear/chromatin localization of FANCM.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16116422
  qualifier: located_in
  review:
    summary: Experimentally determined nuclear localization of FANCM.
    action: ACCEPT
    reason: Direct experimental evidence for nuclear localization.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:20347428
  qualifier: located_in
  review:
    summary: Experimentally determined nuclear localization of FANCM (FANCM-MHF study).
    action: ACCEPT
    reason: Direct experimental evidence for nuclear localization.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:20347429
  qualifier: located_in
  review:
    summary: >-
      Experimentally determined nuclear localization; FANCM is in fact restricted to the chromatin
      fraction under all conditions tested.
    action: ACCEPT
    reason: Direct experimental evidence for nuclear (chromatin) localization.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:29231814
  qualifier: located_in
  review:
    summary: Nuclear localization of FANCM observed in germ cells (oogonia/oocytes).
    action: ACCEPT
    reason: Direct experimental evidence for nuclear localization.
    supported_by:
    - reference_id: PMID:29231814
      supporting_text: FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: EXP
  original_reference_id: PMID:16116422
  qualifier: enables
  review:
    summary: >-
      Experimentally demonstrated ATPase activity of FANCM (mutagenesis of the ATP-binding motif
      abolishes it), underlying its DNA translocation.
    action: ACCEPT
    reason: Direct experimental evidence; ATPase activity is a core catalytic property.
    supported_by:
    - reference_id: PMID:16116422
      supporting_text: FANCM may act as an engine that translocates the FA core complex along DNA.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: EXP
  original_reference_id: PMID:17289582
  qualifier: enables
  review:
    summary: Experimentally demonstrated ATPase activity of FANCM.
    action: ACCEPT
    reason: Direct experimental evidence for the core DNA-dependent ATPase activity.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: EXP
  original_reference_id: PMID:19423727
  qualifier: enables
  review:
    summary: >-
      ATPase activity of FANCM demonstrated; required for cross-linker resistance (fork remodeling)
      but dispensable for FANCD2 monoubiquitination.
    action: ACCEPT
    reason: Direct experimental evidence; the ATPase powers the translocase/remodeling function.
    supported_by:
    - reference_id: PMID:19423727
      supporting_text: The ATPase activity of FANCM is required for cross-linker resistance but not for FANCD2 monoubiquitination and focus formation.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: EXP
  original_reference_id: PMID:20347429
  qualifier: enables
  review:
    summary: >-
      ATP-dependent DNA branch migration by FANCM is abolished in the ATPase-dead K117R mutant,
      demonstrating the DNA-dependent ATPase activity.
    action: ACCEPT
    reason: Direct experimental evidence linking ATP hydrolysis to FANCM branch-migration activity.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: the ATPase deficient FANCMK117R mutant did not display any DNA branch migration activity even with MHF1-MHF2 present
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:20347429
  qualifier: located_in
  review:
    summary: >-
      FANCM is a chromatin-associated protein, detected exclusively in the chromatin fraction; it is
      where FANCM performs fork remodeling and anchors the FA core complex.
    action: ACCEPT
    reason: Direct experimental evidence for chromatin localization.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions
- term:
    id: GO:0036297
    label: interstrand cross-link repair
  evidence_type: IDA
  original_reference_id: PMID:20347429
  qualifier: involved_in
  review:
    summary: >-
      FANCM (via the MHF complex) functions in ICL repair and recovery of forks stalled by
      DNA-lesion/topoisomerase intermediates. Core biological process.
    action: ACCEPT
    reason: Direct experimental evidence; ICL repair is a defining FANCM function.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: MHF1 plays a role in ICL repair and in the recovery of replication forks stalled by topoisomerase I-DNA cleavage intermediates
    - reference_id: PMID:24207054
      supporting_text: The traverse frequency was strongly reduced by inactivation of the translocase and DNA binding activities of the FANCM/MHF complex
- term:
    id: GO:0071821
    label: FANCM-MHF complex
  evidence_type: IPI
  original_reference_id: PMID:20347429
  qualifier: part_of
  review:
    summary: >-
      FANCM forms a discrete complex with the MHF1-MHF2 (CENPS-CENPX) histone-fold heterodimer; MHF
      stimulates FANCM DNA binding and branch migration. FANCM is a core subunit of this complex.
    action: ACCEPT
    reason: Direct evidence for FANCM-MHF complex membership.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: MHF1 has also been identified as a component of the CENPA-CAD complex and named centromere protein S (CENPS)
- term:
    id: GO:1902527
    label: positive regulation of protein monoubiquitination
  evidence_type: IMP
  original_reference_id: PMID:29231814
  qualifier: involved_in
  review:
    summary: >-
      FANCM is required for efficient DNA damage-induced monoubiquitination of FANCD2; patient cells
      with a truncating FANCM mutation show impaired MMC-induced FANCD2 monoubiquitination that is
      rescued by wild-type FANCM. This captures FANCM's positive regulation of FANCD2 (protein)
      monoubiquitination.
    action: ACCEPT
    reason: >-
      Directly supported by loss-of-function and complementation experiments; a core signaling
      function of FANCM in the FA pathway.
    supported_by:
    - reference_id: PMID:29231814
      supporting_text: improved their resistance to MMC re-establishing FANCD2 monoubiquitination
- term:
    id: GO:0000077
    label: DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:18995830
  qualifier: involved_in
  review:
    summary: >-
      FANCM (with FAAP24) is required for ATR/Chk1-mediated checkpoint signaling in response to
      replication stress, independently of the FA core complex: it interacts with the checkpoint
      protein HCLK2, and its DNA translocase activity (dispensable for FANCD2 monoubiquitination) is
      required for efficient Chk1 activation and downstream checkpoint responses. This checkpoint
      role is well documented (also via RPA and TopBP1 chromatin retention) but was not annotated in
      GOA.
    action: NEW
    reason: >-
      A genuine, well-evidenced function of FANCM that the existing GOA annotation set omits.
      Loss-of-function experiments show FANCM/FAAP24 depletion compromises ATR/Chk1 checkpoint
      signaling, and the translocase-dependence separates this activity from the scaffolding role in
      FANCD2 monoubiquitination. GO:0000077 (DNA damage checkpoint signaling) is a correctly-branched
      biological_process term for this role.
    supported_by:
    - reference_id: PMID:18995830
      supporting_text: the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, is required for its role in ATR/Chk1 signaling
    - reference_id: PMID:18995830
      supporting_text: downregulation of FANCM or FAAP24 also compromises ATR/Chk1-mediated checkpoint signaling
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9835411
  qualifier: located_in
  review:
    summary: >-
      Cytosol localization derives from a Reactome PKR-signaling reaction (FA core complex:HSP70s
      binds PKR). FANCM is overwhelmingly nuclear and chromatin-restricted; a cytosolic pool is not a
      characteristic localization for its DNA-repair function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Peripheral pathway-derived localization inconsistent with the well-established nuclear/chromatin
      residence of FANCM; not a core location.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785361
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions; consistent with FANCM's nuclear residence.
    action: ACCEPT
    reason: Consistent with nuclear/chromatin localization; acceptable pathway-based CC annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785732
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785986
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786166
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786171
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788392
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions (ATR phosphorylation of FA proteins).
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785087
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions (FANCM:FAAP24 binds ICL-DNA).
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785126
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions (FA core complex assembly at ICLs).
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785342
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785607
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions (FANCM binds FAAP24).
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6786155
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions.
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6788385
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome FA pathway reactions (ATR:ATRIP recruitment to ICL-DNA).
    action: ACCEPT
    reason: Consistent with nuclear localization of FANCM.
- term:
    id: GO:0000712
    label: resolution of meiotic recombination intermediates
  evidence_type: IMP
  original_reference_id: PMID:20347428
  qualifier: involved_in
  review:
    summary: >-
      FANCM regulates recombination outcomes by processing/branch-migrating recombination
      intermediates and suppressing crossovers; in germ cells it is expressed along pachytene
      chromosomes. Consistent with a meiotic recombination-intermediate resolution role, though for
      human FANCM this is a tissue-specific/secondary function relative to its replication-fork role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimental (IMP) annotation by the curator; FANCM's anti-crossover/recombination-intermediate
      processing activity supports a meiotic role, but it is non-core relative to ICL repair and fork
      remodeling. Not removed, per deference to the experimental annotation.
    supported_by:
    - reference_id: PMID:29231814
      supporting_text: FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination.
- term:
    id: GO:0031297
    label: replication fork processing
  evidence_type: IMP
  original_reference_id: PMID:20347428
  qualifier: involved_in
  review:
    summary: >-
      FANCM remodels branched DNA structures and protects/processes stalled replication forks; MHF
      stimulates FANCM's replication fork remodeling. A core FANCM biological process.
    action: ACCEPT
    reason: >-
      Directly supported experimental annotation; fork remodeling/processing is a central FANCM
      function driven by its translocase activity.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: MHF stimulates DNA binding and replication fork remodeling by FANCM.
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      FANCM is a component of the Fanconi anemia nuclear core complex (with FANCA/B/C/E/F/G/L,
      FAAP24, FAAP100, CENPS/CENPX), which it anchors to chromatin. Core complex membership.
    action: ACCEPT
    reason: Direct experimental evidence for FA core complex membership.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: FANCM-MHF associates with the Fanconi anemia (FA) core complex, promotes FANCD2 monoubiquitination in response to DNA damage, and suppresses sister-chromatid exchanges.
- term:
    id: GO:0071821
    label: FANCM-MHF complex
  evidence_type: IDA
  original_reference_id: PMID:20347428
  qualifier: part_of
  review:
    summary: >-
      FANCM forms the FANCM-MHF complex with the CENPS-CENPX histone-fold dimer; this complex
      stimulates DNA binding and fork remodeling by FANCM.
    action: ACCEPT
    reason: Direct experimental evidence for FANCM-MHF complex membership.
    supported_by:
    - reference_id: PMID:20347428
      supporting_text: MHF stimulates DNA binding and replication fork remodeling by FANCM.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IDA
  original_reference_id: PMID:20347429
  qualifier: enables
  review:
    summary: >-
      FANCM binds chromatin and is required for chromatin association of the FA core complex; it is
      detected exclusively in the chromatin fraction. Chromatin binding is central to its
      scaffolding/recruitment role.
    action: ACCEPT
    reason: Direct experimental evidence; chromatin binding underlies FANCM's anchoring function.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20347429
  qualifier: enables
  review:
    summary: >-
      IPI capturing the FANCM-CENPS (MHF1) interaction. Biologically meaningful (FANCM-MHF complex)
      but the generic "protein binding" term is uninformative and represented by the complex terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) is uninformative; the specific FANCM-CENPS/MHF interaction is
      captured by the FANCM-MHF complex annotation.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: MHF1 has also been identified as a component of the CENPA-CAD complex and named centromere protein S (CENPS)
- term:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  evidence_type: IDA
  original_reference_id: PMID:20347429
  qualifier: part_of
  review:
    summary: >-
      FANCM is a component of the FA nuclear core complex; MHF1/MHF2 are identified as novel
      components of this complex via FANCM.
    action: ACCEPT
    reason: Direct experimental evidence for FA core complex membership.
    supported_by:
    - reference_id: PMID:20347429
      supporting_text: These results thus identify MHF1 and MHF2 as novel components of the FA core complex.
core_functions:
- description: >-
    ATP-dependent DNA translocase that binds branched DNA and catalyzes ATP-driven branch migration
    of stalled/regressed replication forks and Holliday junctions, remodeling branched
    replication/recombination intermediates; this activity is stimulated by the MHF1-MHF2
    (CENPS-CENPX) histone-fold dimer and is required for replication fork protection and ICL repair.
  molecular_function:
    id: GO:0015616
    label: DNA translocase activity
  directly_involved_in:
  - id: GO:0031297
    label: replication fork processing
  - id: GO:0036297
    label: interstrand cross-link repair
  locations:
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0071821
    label: FANCM-MHF complex
  supported_by:
  - reference_id: PMID:20347429
    supporting_text: FANCM has a DNA branch migration activity that can process branched DNA structures such as a movable replication fork (MRF)
  - reference_id: PMID:20347428
    supporting_text: MHF stimulates DNA binding and replication fork remodeling by FANCM.
  - reference_id: PMID:18206976
    supporting_text: purified FANCM binds to Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner
  - reference_id: PMID:24207054
    supporting_text: The traverse frequency was strongly reduced by inactivation of the translocase and DNA binding activities of the FANCM/MHF complex
- description: >-
    Chromatin-binding scaffold that, together with FAAP24 and the MHF dimer, anchors the Fanconi
    anemia core complex to chromatin at stalled replication forks and interstrand crosslinks,
    enabling efficient DNA damage-induced monoubiquitination of the FANCD2-FANCI complex and
    activation of the FA pathway.
  molecular_function:
    id: GO:0003682
    label: chromatin binding
  directly_involved_in:
  - id: GO:1902527
    label: positive regulation of protein monoubiquitination
  - id: GO:0036297
    label: interstrand cross-link repair
  locations:
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0043240
    label: Fanconi anaemia nuclear complex
  supported_by:
  - reference_id: PMID:19423727
    supporting_text: FANCM is rather responsible for the recruitment of the FA core complex to the chromatin
  - reference_id: PMID:29231814
    supporting_text: improved their resistance to MMC re-establishing FANCD2 monoubiquitination
proposed_new_terms: []
suggested_questions:
- question: >-
    Is the ATP-dependent DNA translocase/branch-migration activity of human FANCM required for
    replication traverse of ICLs and fork reversal in vivo, as distinct from its
    (ATPase-independent) scaffolding role in FANCD2 monoubiquitination?
- question: >-
    What is the direct in vivo substrate spectrum of the FANCM-MHF-FAAP24 assembly at stalled forks
    (regressed forks, D-loops, Holliday junctions), and how is activity partitioned between fork
    remodeling and checkpoint signaling?
suggested_experiments:
- description: >-
    Separation-of-function analysis in FANCM-null human cells comparing wild-type, ATPase-dead
    (K117R), C-terminal (FAAP24-binding) deletion, and MHF-binding mutants for ICL traverse, fork
    reversal, FANCD2 monoubiquitination, ATR signaling, and SCE/crossover suppression.
- description: >-
    Single-molecule or reconstituted-fork biochemistry with purified FANCM +/- MHF1-MHF2 and FAAP24
    to quantify translocation processivity and branch-migration directionality on defined fork/HJ
    substrates.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  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: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16116422
  title: A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi
    anemia complementation group M.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding paper identifying FANCM (FAAP250) as mutated in FA complementation group M; establishes
      DNA-dependent ATPase/translocase activity, essential role in FANCD2 monoubiquitination, and
      hyperphosphorylation on DNA damage. Verified against cached abstract/full text.
- id: PMID:17289582
  title: Identification of FAAP24, a Fanconi anemia core complex protein that interacts
    with FANCM.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes the FANCM-FAAP24 heterodimer (C-terminal ERCC4-like region), DNA-structure binding,
      and recruitment of the FA core complex to damaged DNA. Supports complex-membership annotations.
- id: PMID:18206976
  title: The Fanconi anemia protein FANCM can promote branch migration of Holliday
    junctions and replication forks.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary biochemistry (Gari et al. 2008): purified FANCM binds Holliday junctions and
      replication forks with high specificity and promotes ATP-dependent branch migration, dissociating
      recombination intermediates through 2.6 kb of DNA. Direct experimental support for the four-way
      junction binding/branch-migration (translocase) annotations. Abstract cached.
- id: PMID:18995830
  title: FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently
    of the Fanconi anemia core complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Collis et al. 2008: FANCM/FAAP24 interact with HCLK2 and are required for ATR/Chk1-mediated
      checkpoint signaling independently of the FA core complex; the FANCM translocase activity
      (dispensable for FA pathway activation) is required for this checkpoint role. Basis for the NEW
      DNA damage checkpoint signaling annotation. Abstract cached.
- id: PMID:24207054
  title: The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand
    crosslinks.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Huang et al. 2013 (full text): single-molecule DNA-fiber assay shows FANCM/MHF translocase and
      DNA-binding activities promote replication traverse of ICLs, allowing DNA synthesis to continue
      past crosslinks without lesion repair. Corroborates the translocase core function and ICL-repair
      annotations.
- id: PMID:19423727
  title: Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely
    characterize Fanconi anemia complementation group M.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available. Key for separation of functions: ATPase required for cross-linker
      resistance but not FANCD2 monoubiquitination; FANCM recruits FA core complex to chromatin; only
      translocase (not helicase) activity observed; not essential for RAD51-dependent HR.
- id: PMID:20347428
  title: A histone-fold complex and FANCM form a conserved DNA-remodeling complex
    to maintain genome stability.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the FANCM-MHF DNA-remodeling complex; MHF stimulates FANCM DNA binding and fork
      remodeling; both recruited to ICL-stalled forks; FANCM-MHF part of FA core complex and BRAFT
      supercomplex; suppresses SCE. Abstract cached.
- id: PMID:20347429
  title: MHF1-MHF2, a histone-fold-containing protein complex, participates in the
    Fanconi anemia pathway via FANCM.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available. Identifies MHF1/MHF2 (CENPS/CENPX) as FA core complex components; MHF binds
      DNA and stimulates FANCM branch migration (ATP- and K117-dependent); FANCM restricted to
      chromatin fraction. Central to DNA-binding, chromatin, complex, and translocase annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput interactome map; source of a generic protein-binding (TRIM27) IPI. No
      gene-specific functional insight; annotation marked over-annotated.
- id: PMID:29231814
  title: A homozygous FANCM mutation underlies a familial case of non-syndromic primary
    ovarian insufficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available. Biallelic FANCM truncation (p.Gln1701*) causes POI with impaired
      MMC-induced FANCD2 monoubiquitination rescued by WT FANCM; germ-cell/pachytene expression;
      DNA-damage (not replication-inhibition) specificity. Supports FANCD2-monoub and meiotic
      annotations.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale binary interactome (Y2H) map; source of a generic protein-binding (EPN2 isoform)
      IPI. No specific functional content; annotation marked over-annotated.
- id: PMID:32769987
  title: DONSON and FANCM associate with different replisomes distinguished by replication
    timing and chromatin domain.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows FANCM (as a DNA translocase) associates with a distinct class of replisomes prominent in
      late S phase/heterochromatin. Corroborates translocase identity and replication-fork context;
      cited protein-binding (MCM2) IPI itself is uninformative.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale interactome study; source of a generic protein-binding (FAAP24) IPI. FAAP24
      interaction is real but better captured by complex terms; annotation marked over-annotated.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale multimodal cell-map interactome; source of a generic protein-binding (FAAP24) IPI.
      No gene-specific functional detail; annotation marked over-annotated.
- id: Reactome:R-HSA-6785087
  title: FANCM:FAAP24 and APITD1:STRA13 bind ICL-DNA
  findings: []
- id: Reactome:R-HSA-6785126
  title: FA core complex assembles at DNA interstrand crosslinks (ICLs)
  findings: []
- 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-6785607
  title: FANCM binds FAAP24
  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-9835411
  title: FA core complex:HSP70s binds PKR
  findings: []