FANCM is an ATP-dependent DNA translocase related to archaeal Hef and the yeast Mph1/Fml1 proteins. Its N-terminal motor recognizes branched nucleic-acid structures and drives branch migration of replication forks and Holliday junctions. The MHF1βMHF2 (CENPSβCENPX) histone-fold complex stimulates DNA binding and fork remodeling, while the C-terminal ERCC4/XPF-like region associates with FAAP24. Purified human FANCM with FAAP24 also disassembles DNA:RNA flaps and telomeric R-loops in ATP-dependent reactions. These activities support stalled-fork processing, interstrand cross-link repair and suppression of inappropriate recombination. Fly and fission-yeast experiments establish noncrossover synthesis-dependent strand annealing as a conserved function of the family. FANCM recruits Fanconi anemia core-complex proteins to chromatin, promoting damage-induced FANCD2 monoubiquitination through a structural role distinct from the ubiquitin-transfer chemistry of the core ligase. It is predominantly nuclear and becomes hyperphosphorylated after DNA damage. Human FANCM is expressed in developing ovarian germ cells; a homozygous truncating variant has been linked to familial non-syndromic primary ovarian insufficiency. Its annotated natural splice products contain 2048, 669 and 2022 residues: the 669-residue product lacks the C-terminal interaction regions, and the 2022-residue product lacks residues 228β253 within the motor region.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036297 interstrand cross-link repair | IBA GO_REF:0000033 | ACCEPT | Summary: FANCM participates directly in interstrand cross-link repair. Reason: The verified PAINT node carries a term-specific IBD with Fml1, Mph1 and human FANCM descendant evidence, including legitimate target self-WITH. Human FANCM performs branched-DNA remodeling and helps assemble the DNA-associated repair machinery, rather than merely being a passive repair substrate. Human MHF/FANCM biochemical and cellular results in PMID:20347428 and PMID:20347429, together with the explicitly modeled early FANCM:FAAP24/MHF ICL context, support this conserved process. Donor count and self-inclusion are not adverse evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000361481 SUPPORTS TRANSFER Authentic PTHR14025 v19 tree and MSA place human PTN002493637 below this node; the term-specific IBD for GO:0036297 is present. Fml1, Mph1 and human descendant evidence supports the inherited repair role; target self-WITH is expected. Supporting Evidence: PMID:20347428 FANCM and MHF are rapidly recruited to forks stalled by DNA interstrand crosslinks, and both are required for cellular resistance to such lesions. Reactome:R-HSA-6785087 |
| GO:0000400 four-way junction DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: FANCM recognizes four-way DNA junctions. Reason: The authentic PAINT assertion lies on the verified target ancestral path and is supported by Fml1 experimental junction binding. Human FANCM fragments and complexes bind Holliday-junction substrates: PMID:20347428 reports FANCM residues 1β754 and MHF-dependent cooperative binding. The full protein, engineered fragment and natural 669-residue product are not treated as interchangeable. This binding assertion is independent of whether the motor is described as a conventional duplex helicase. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000361481 SUPPORTS TRANSFER Authentic PTHR14025 v19 tree and MSA place human PTN002493637 below this node; the term-specific IBD for GO:0000400 is present. Fml1 is the positive experimental descendant source; one donor is not weak evidence. Supporting Evidence: PMID:20347429 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 PMID:18206976 purified FANCM binds to Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner |
| GO:0009378 four-way junction helicase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Four-way-junction helicase activity describes the supported junction-processing output. Reason: The actual GO definition concerns ATP-driven unwinding of DNA containing four-way junctions. Fml1 ΞC experiments in PMID:18851838 demonstrate ATP-dependent migration/dissociation of mobile Holliday junctions and distinguish limited unwinding of static substrates. Human FANCM has ATP-dependent branch-migration activity, supported by PMID:18206976 and independently by movable-fork assays in PMID:20347429. This structure-specific output is compatible with a branchpoint translocase and does not require a claim of unrestricted conventional duplex helicase activity. The authentic term-specific PTN000361481 IBD and human descent were verified. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000361481 SUPPORTS TRANSFER Authentic PTHR14025 v19 tree and MSA place human PTN002493637 below this node; the term-specific IBD for GO:0009378 is present. Fml1 experiments support junction processing; human branch migration corroborates this structure-specific activity. Supporting Evidence: PMID:20347429 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 PMID:18206976 FANCM can dissociate large recombination intermediates, via branch migration of Holliday junctions through 2.6 kb of DNA |
| GO:0043138 3'-5' DNA helicase activity | IBA GO_REF:0000033 | MODIFY | Summary: Use the demonstrated DNA translocase mechanism for human FANCM. Reason: The verified PTN000361481 IBD is supported by Drosophila Fancm and yeast Mph1. The donor chemistry is positive: PMID:27466228 tests an engineered Drosophila Fancm truncation lacking 840 C-terminal residues, with ATP/K84M and 3β² versus 5β² tail controls, and observes limited duplex unwinding. The verified Mph1 abstract in PMID:15634678 also reports 3β²β5β² DNA helicase activity; its full original remained unavailable. Human FANCM is independently supported as an ATP-driven branchpoint motor in PMID:20347429, and RNAβDNA flap homology controls in PMID:26593718 distinguish branch migration from simple strand separation. GO:0015616 captures that established target mechanism without declaring the donors incorrect, the ancestral placement wrong, or all latent human duplex unwinding disproved. The refinement concerns the target activity description, not loss of the conserved motor. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000361481 SUPPORTS TRANSFER Authentic PTHR14025 v19 tree and MSA place human PTN002493637 below this node; the term-specific IBD for GO:0043138 is present. Fly and Mph1 positive chemistry supports a conserved ATP-dependent DNA motor; target-specific mechanism is represented more directly by DNA translocase activity. Proposed replacements: DNA translocase activity Supporting Evidence: PMID:19423727 for FANCM only translocase activity was observed |
| GO:0045003 double-strand break repair via synthesis-dependent strand annealing | IBA GO_REF:0000033 | ACCEPT | Summary: Retain conserved participation in synthesis-dependent strand annealing. Reason: The authentic PTN000361481 IBD is grounded in fly Fancm and fission-yeast Fml1. In PMID:25205745, a Drosophila gap-repair assay distinguishes completed SDSA products and detects an approximately 50% reduction in Fancm mutants. PMID:22723423 combines Fml1 D-loop displacement and catalytic-mutant/noncrossover genetics; PMID:28977643 supports the centromeric context while presenting SDSA as its mechanistic model. These are roles in processing recombination intermediates, not solely downstream necessity. Human FANCM has the conserved branchpoint motor; this is an IBA conclusion, not a claim that the donor assays were performed in human cells. Normal RAD51 foci in one patient-cell context do not refute downstream SDSA participation. No evidence of target-specific loss of this inherited function was established. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000361481 SUPPORTS TRANSFER Authentic PTHR14025 v19 tree and MSA place human PTN002493637 below this node; the term-specific IBD for GO:0045003 is present. Positive fly gap-repair and Fml1 intermediate-processing experiments support transfer; no target-specific loss established. Supporting Evidence: PMID:19423727 FANCM may have a more regulatory function in the homologous recombination process |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | ACCEPT | Summary: Retain the broad nucleic-acid-binding mapping. Reason: IPR011545 matches residues 105β254 of displayed human Q8IYD8 and maps to nucleic acid binding. Actual human DNA-binding and branch-migration assays support this broad electronic assertion. DNA substrates and RNAβDNA hybrids have been tested, so nucleic-acid binding is not rejected merely for breadth; no independent RNA-only substrate preference is inferred. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: DNA binding is supported independently of the ERCC4-domain prediction. Reason: IPR006166 is an actual ERCC4-domain match at residues 1841β1948 of displayed Q8IYD8 and maps to DNA binding. The term is independently supported by FANCM binding to branched DNA in PMID:20347428 and PMID:20347429. The ERCC4 fold is not used to assign nuclease chemistry, and the match is absent from the short natural 669-residue product; whole-gene support does not establish identical binding properties for every product. Supporting Evidence: PMID:20347429 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 |
| GO:0003724 RNA helicase activity | IEA GO_REF:0000003 | MODIFY | Summary: Describe the established motor as DNA translocase activity, including RNAβDNA branch migration. Reason: The electronic row derives from EC 3.6.4.13, RNA helicase. Human FANCM:FAAP24 directly displaces DNA:RNA flaps (PMID:26593718, Figure 6 and Biochemical Analysis) and plasmid telomeric R-loops (PMID:31138795, Figure 7b and In vitro R-loop resolution assays). The former reports failure of a translocase-dead protein and inhibition by ATP-Ξ³-S; heterology preventing branch migration blocks displacement. Its inspected text does not name that protein K117R. These reactions establish hybrid remodeling by a DNA-tracking branchpoint motor, not autonomous RNA-duplex helicase activity. Refine the molecular function to DNA translocase activity. The demonstrated hybrid-substrate process is represented separately by GO:0062176 in the core and the new R-loop-processing proposal. Proposed replacements: DNA translocase activity Supporting Evidence: PMID:19423727 for FANCM only translocase activity was observed |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is integral to the FANCM motor. Reason: The target contains the actual IPR011545 and IPR044749 N-terminal matches (105β254 and 89β270). Human FANCM ATPase/branch-migration experiments and the engineered K117R control in PMID:20347429 corroborate ATP-dependent motor function; a domain label alone is not the basis for acceptance. The natural 2022-residue product deletes displayed residues 228β253 within this region, and its catalytic equivalence has not been established. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Retain the supported nuclear localization. Reason: The literal UniProt SL-0191 assertion maps to nucleus. Human nuclear-extract purification of FANCM-containing complexes in PMID:20347429, HPA nucleoplasmic staining, and explicit Reactome nuclear entities provide convergent support. Nucleus retains the appropriate breadth and does not assert that all molecules are freely soluble or that all natural products share the same localization. |
| GO:0006281 DNA repair | IEA GO_REF:0000120 | ACCEPT | Summary: DNA repair is a supported broad electronic process annotation. Reason: The combined IEA source contains IPR039686 and ARBA00029008. The actual rule has matching IPR011335/Eukaryota and IPR014001/IPR039686/IPR044749 clauses; its consequent is GO:0006281. Independent human FANCM branch migration and DNA-damage-response studies support active DNA repair participation. The two mappings are not counted as independent experiments, and repair is not restricted to every chemistry performed by an associated complex. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000116 | ACCEPT | Summary: ATP hydrolysis is directly supported for FANCM. Reason: RHEA:13065 explicitly describes ATP + water to ADP, phosphate and proton. In PMID:20347429, human FANCM hydrolyzes ATP with DNA cofactors and the K117R control is defective; MHF stimulates branch migration without increasing ATPase potency under the tested conditions. The hydrolysis chemistry is distinct from the choice of DNA or RNAβDNA substrate and does not alone establish RNA helicase activity. |
| GO:0035825 homologous recombination | IEA GO_REF:0000117 | MODIFY | Summary: Retain the historical ARBA source record as retired, with its biological interpretation refined to independently supported SDSA. Reason: The saved historical GOA row identifies ARBA:ARBA00027491 as the source of this GO_REF:0000117 assertion. That exact target-source assertion is absent from the accepted fresh snapshot, while the independent GO:0045003 IBA remains active. Retired here records a scoped historical-source lifecycle decision and preserves the original record; it does not assert that the ARBA rule was deleted or that homologous recombination is absent. The official ARBA rule is still retrievable and asserts GO:0035825, but its historical target eligibility and the reason for this target-row disappearance have not been established. Independently of that lifecycle, positive fly gap-repair experiments support completion of SDSA (PMID:25205745); Fml1 D-loop displacement, catalytic-mutant genetics and noncrossover outcomes support the conserved mechanism (PMID:22723423), with centromeric SDSA explicitly a model in PMID:28977643. GO:0045003 therefore states the supported repair contribution more precisely and is already represented by the active IBA; no duplicate NEW annotation is proposed. GO:0035825 describes equal-material exchange, but its reciprocal-recombination synonym is narrow and crossover synonym related, so neither the definition nor the lack of an is_a link is treated as proof that FANCM cannot participate in broader homologous recombination. The inherited PMID:19423727 quotation about normal RAD51 foci remains exact: normal foci or nonessentiality does not negate downstream intermediate processing. Its original full Methods/Results were not recovered in these lanes. Proposed replacements: double-strand break repair via synthesis-dependent strand annealing Supporting Evidence: PMID:19423727 normal Rad51 foci, indicating that FANCM is not essential for homologous recombination repair |
| GO:0043138 3'-5' DNA helicase activity | IEA GO_REF:0000002 | MODIFY | Summary: Use the demonstrated DNA translocase mechanism for human FANCM. Reason: The actual IPR039686 FANCM/Mph1 insert-domain match spans residues 298β413 and maps to this helicase term. The donor chemistry is positive: PMID:27466228 tests an engineered Drosophila Fancm truncation lacking 840 C-terminal residues, with ATP/K84M and 3β² versus 5β² tail controls, and observes limited duplex unwinding. The verified Mph1 abstract in PMID:15634678 also reports 3β²β5β² DNA helicase activity; its full original remained unavailable. Human FANCM is independently supported as an ATP-driven branchpoint motor in PMID:20347429, and RNAβDNA flap homology controls in PMID:26593718 distinguish branch migration from simple strand separation. GO:0015616 captures that established target mechanism without declaring the donors incorrect, the ancestral placement wrong, or all latent human duplex unwinding disproved. The refinement concerns the target activity description, not loss of the conserved motor. Proposed replacements: DNA translocase activity Supporting Evidence: PMID:19423727 for FANCM only translocase activity was observed |
| GO:0005515 protein binding | IPI PMID:17289582 Identification of FAAP24, a Fanconi anemia core complex prot... | KEEP AS NON CORE | Summary: FANCM associates with FAAP24. Reason: PMID:17289582 explicitly reports FAAP24 association with the FANCM C-terminal region and describes FAAP24 targeting FANCM to damaged-DNA-like structures; its full Methods/Results were not recovered. PMID:20347428 independently recovers native FANCMβFAAP24 assemblies and distinguishes them from FANCMβMHF pools. These data support this interaction, but do not establish FAAP24 as cargo recruited to chromatin by FANCM. The separately supported FA core recruitment function therefore does not supply an evidence-matched adaptor replacement for this particular IPI row. Retain as non-core under the standing project exception. Supporting Evidence: PMID:17289582 associates with the C-terminal region of FANCM, and is a component of the FA core complex |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: The human interactome screen supports a FANCM-TRIM27 interaction. Reason: The PMID:25416956 IntAct target records identify Q8IYD8 with P14373/TRIM27 in two-hybrid screening and validated two-hybrid retesting. The original Methods/Results describe sequence confirmation and repeated pairwise tests; orthogonal validation is described at dataset/subset level and is not claimed specifically for this pair. Retain the supported interaction as non-core under the project exception. A TRIM27 enzymatic or substrate relationship is not established by these records. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI supports association of FANCM with the tested EPN2 isoform. Reason: PMID:32296183 target records identify EPN2 O95208-2 with FANCM Q8IYD8 in two-hybrid screens and validated retesting. Original Methods/Results describe quadruplicate pairwise retesting and sequence confirmation. This establishes the reported biophysical interaction, not an endocytic function of FANCM or equivalence among all EPN2/FANCM natural products. Retain as non-core under the standing generic-binding exception. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32769987 DONSON and FANCM associate with different replisomes disting... | KEEP AS NON CORE | Summary: FANCM associates with MCM2-containing stressed replisomes. Reason: PMID:32769987 Figure 2 and Methods show sequential immunoprecipitation from benzonase-digested human chromatin and FANCM-MCM2 proximity ligation, increased after psoralen/UVA crosslinks. FANCM-containing replisomes are distinct from DONSON-containing pools and biased toward late S phase. These assays support complex association/proximity; they do not demonstrate an isolated binary contact or assign MCM helicase catalysis to FANCM. Retain the supported generic binding as non-core under the project exception. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex detects FANCM association with FAAP24. Reason: The PMID:33961781 target records include FAAP24 Q9BTP7 and FANCM Q8IYD8 in anti-tag coimmunoprecipitation/AP-MS records. The inspected original Methods use exogenous affinity-tagged baits in 293T and HCT116 cells; the short target export does not by itself assign each record to a cell line. These are association data rather than purified binary-binding or functional assays. Retain as non-core under the project exception. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: The U2OS AP-MS network reports a FANCM-FAAP24 association. Reason: The author-linked PMID:40205054 NDEx AP-MS network contains the FAAP24-FANCM edge with the corresponding Ensembl gene identities. Original Methods describe C-terminal HA-Flag-tagged bait purification and interaction filtering in U2OS cells. The supplementary-table download returned recaptcha HTML, so no workbook-level target verification is claimed; the actual author-linked network supplies the target record. Retain this supported association as non-core without inferring a new molecular function from multimodal proximity or assembly membership. Supporting Evidence: |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas supports nucleoplasmic FANCM. Reason: The official HPA record identifies FANCM/ENSG00000187790, supported antibody HPA055144 and nucleoplasm in A-431, PC-3 and U-2 OS cells. Actual A-431 and U-2 OS composite images were inspected: green staining is enriched within the blue nuclear area; PC-3 pixels were not inspected. The antigen maps exactly to displayed residues 1802β1886, absent from the 669-residue product and retained in the longer splice product. The images therefore do not establish localization of all three products or distinguish the two antigen-containing products. Supporting Evidence: HPA:ENSG00000187790 |
| GO:0005634 nucleus | EXP PMID:16116422 A human ortholog of archaeal DNA repair protein Hef is defec... | ACCEPT | Summary: Nucleus is a well-supported location of human FANCM. Reason: Retain the experimental annotation by curator deference and independent direct human evidence: PMID:20347428 purifies FANCM from HeLa nuclear extract and images recruitment to nuclear crosslinks; PMID:20347429 detects FANCM in chromatin. The original PMID:16116422 cache is abstract-only and its detailed localization assay was not recovered. Acceptance does not certify an independent full-text reading of that original experiment. |
| GO:0005634 nucleus | EXP PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: Human FANCM occupies the nucleus and is recruited to nuclear crosslink sites. Reason: PMID:20347428 identifies FANCM-containing complexes in HeLa nuclear extract and detects FANCM at psoralen/UVA-induced nuclear ICL sites within 15 minutes, preferentially in S-phase cells. Retain the broad nuclear location alongside the more specific chromatin annotations. Supporting Evidence: |
| GO:0005634 nucleus | EXP PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: Human FANCM is nuclear and chromatin associated. Reason: PMID:20347429 Figure 1 and Results identify FANCM in nuclear preparations and the HeLa chromatin pellet under untreated, MMC-treated and HU-treated conditions. The inherited quotation is limited to those fractionation conditions; it does not rule out other cellular pools. Supporting Evidence: PMID:20347429 FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions |
| GO:0005634 nucleus | EXP PMID:29231814 A homozygous FANCM mutation underlies a familial case of non... | ACCEPT | Summary: FANCM is detected in nuclei of human ovarian germ cells. Reason: PMID:29231814 Results, Figure 2 and immunohistochemistry Methods report nuclear staining in oogonia and oocytes, including pachytene chromosomes. Germ-cell/meiotic markers and nonimmune IgG controls are described. This supports nuclear localization, while localization alone does not establish a specific meiotic-resolution reaction or natural-product-specific distribution. Supporting Evidence: PMID:29231814 FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. |
| GO:0016887 ATP hydrolysis activity | EXP PMID:16116422 A human ortholog of archaeal DNA repair protein Hef is defec... | ACCEPT | Summary: ATP hydrolysis is a demonstrated catalytic property of human FANCM. Reason: Retain the PMID:16116422 experimental annotation by curator deference and independent target-specific biochemical evidence. PMID:20347429 directly measures DNA-dependent ATP hydrolysis and uses K117R and nonhydrolyzable-ATP controls for coupled branch migration. The original cache contains the abstract, not the operative ATPase Methods/Results; the inherited engine/translocation quotation is a mechanistic proposal rather than a hydrolysis measurement. The correct ATPase activity is retained without claiming unseen source details or processive duplex-helicase activity. Supporting Evidence: PMID:16116422 FANCM may act as an engine that translocates the FA core complex along DNA. |
| GO:0016887 ATP hydrolysis activity | EXP PMID:17289582 Identification of FAAP24, a Fanconi anemia core complex prot... | ACCEPT | Summary: ATP hydrolysis is a demonstrated catalytic property of human FANCM. Reason: Retain the PMID:17289582 experimental annotation by curator deference and independent target-specific biochemical evidence. PMID:20347429 directly measures DNA-dependent ATP hydrolysis and uses K117R and nonhydrolyzable-ATP controls for coupled branch migration. The original cache is abstract-only and its ATPase experiments were not recovered; the abstractβs FAAP24-association result is not itself an ATP-hydrolysis assay. The correct ATPase activity is retained without claiming unseen source details or processive duplex-helicase activity. |
| GO:0016887 ATP hydrolysis activity | EXP PMID:19423727 Impaired FANCD2 monoubiquitination and hypersensitivity to c... | ACCEPT | Summary: ATP hydrolysis is a demonstrated catalytic property of human FANCM. Reason: Retain the PMID:19423727 experimental annotation by curator deference and independent target-specific biochemical evidence. PMID:20347429 directly measures DNA-dependent ATP hydrolysis and uses K117R and nonhydrolyzable-ATP controls for coupled branch migration. The cache is flagged full text but contains selected Introduction/Discussion without operative Results/Methods; its separation of ATPase-dependent crosslink resistance from FANCD2 monoubiquitination was read as discussion, not as independently audited assay data. The correct ATPase activity is retained without claiming unseen source details or processive duplex-helicase activity. Supporting Evidence: PMID:19423727 The ATPase activity of FANCM is required for cross-linker resistance but not for FANCD2 monoubiquitination and focus formation. |
| GO:0016887 ATP hydrolysis activity | EXP PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: Human FANCM hydrolyzes ATP to power DNA remodeling. Reason: PMID:20347429 Figure 4E/F and Results directly measure DNA-dependent ATP hydrolysis. K117R is defective, and branch migration requires ATP rather than ATP-gamma-S or AMP-PNP. MHF stimulates branch migration without enhancing measured FANCM ATPase potency. Retain the catalytic activity; these controls do not establish a conventional directional duplex-unwinding helicase. Supporting Evidence: PMID:20347429 the ATPase deficient FANCMK117R mutant did not display any DNA branch migration activity even with MHF1-MHF2 present |
| GO:0000785 chromatin | IDA PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: FANCM is associated with chromatin in the tested human cells. Reason: PMID:20347429 Results and Figure 1F report FANCM in the HeLa chromatin pellet before treatment and after MMC or HU. MHF1 depletion reduces chromatin-associated FANCM. This supports chromatin as a central operating location, without claiming that all human cell types or natural products lack other pools. Supporting Evidence: PMID:20347429 FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions |
| GO:0036297 interstrand cross-link repair | IDA PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: FANCM contributes DNA remodeling and repair-factor recruitment to interstrand crosslink repair. Reason: PMID:20347429 supports a functional FANCM-MHF machinery through human complex biochemistry, MHF perturbation and crosslink-response experiments; its quoted phenotype is specifically MHF1-centered. Independent human knockout/complementation experiments in PMID:23333308 support FANCM-dependent recombination-independent ICL repair and recruitment of repair factors, with loss of these functions in the K117R background. The retained PMID:24207054 quote concerns replication traverse, which can leave the crosslink unrepaired and is not by itself proof of lesion removal. Supporting Evidence: PMID:20347429 MHF1 plays a role in ICL repair and in the recovery of replication forks stalled by topoisomerase I-DNA cleavage intermediates PMID:24207054 The traverse frequency was strongly reduced by inactivation of the translocase and DNA binding activities of the FANCM/MHF complex |
| GO:0071821 FANCM-MHF complex | IPI PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: FANCM associates with the MHF1-MHF2 heterodimer. Reason: PMID:20347429 affinity purification, coimmunoprecipitation and co-fractionation establish FANCM-MHF association, while purified-protein pull-down identifies direct FANCM-MHF1 contact. The inherited CENPS identity quotation is retained but is not itself the membership assay. MHF-enhanced branch migration supplies functional context. Supporting Evidence: PMID:20347429 MHF1 has also been identified as a component of the CENPA-CAD complex and named centromere protein S (CENPS) |
| GO:1902527 positive regulation of protein monoubiquitination | IMP PMID:29231814 A homozygous FANCM mutation underlies a familial case of non... | ACCEPT | Summary: FANCM promotes efficient damage-induced FANCD2 monoubiquitination. Reason: PMID:29231814 reports impaired MMC-induced FANCD2 monoubiquitination in cells bearing the human p.Gln1701* allele and improvement after wild-type FANCM complementation. Residual responses to HU/aphidicolin and the tested truncated product limit a universal necessity claim. Together with chromatin-recruitment evidence this supports positive regulation, without assigning the FANCL/UBE2T-catalyzed ubiquitin-transfer reaction to FANCM. Supporting Evidence: PMID:29231814 improved their resistance to MMC re-establishing FANCD2 monoubiquitination |
| GO:0000077 DNA damage checkpoint signaling | IMP PMID:18995830 FANCM and FAAP24 function in ATR-mediated checkpoint signali... | UNDECIDED | Summary: The inherited FANCM checkpoint proposal needs context-specific adjudication. Reason: PMID:18995830 reports FANCM/FAAP24-HCLK2 association and translocase-dependent checkpoint defects in its accessible abstract, but the operative Methods/Results were not recovered. This supports a plausible signal-generating/recruitment role rather than FANCM being merely a checkpoint substrate; it does not independently settle the participation mechanism. In contrast, the inspected PMID:23333308 HCT116 knockout study finds no detectable FANCM-dependent CHK1-phosphorylation defect after MMC, UV or HU, and explicitly discusses possible adaptation versus acute-depletion effects. PMID:29231814 p.Gln1701* cells also retain the tested MMC CHK1 response, but that truncated allele is not a clean null. These contexts do not prove that FANCM never participates in checkpoint signaling. Retire the inherited authored proposal while keeping its object, position and both quotations, and mark its scientific assessment UNDECIDED pending direct reconciliation of the original assays and mechanism. This is withdrawal of the broad authored assertion, not withdrawal of a current imported annotation and not biological negation. Comparator and GO-CAM checks do not independently establish a missing-annotation gap. Supporting Evidence: PMID:18995830 the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, is required for its role in ATR/Chk1 signaling PMID:18995830 downregulation of FANCM or FAAP24 also compromises ATR/Chk1-mediated checkpoint signaling |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9835411 | KEEP AS NON CORE | Summary: Retain the explicit cytosolic FANCM participant as a contextual location. Reason: Reactome:R-HSA-9835411 includes FANCM through the cytosolic FA-core/HSP70 assembly and FANCM:FAAP24 complex 9835416. Its FANCM entity 420802 is human Q8IYD8, residues 1β2048, with its own cytosol compartment. The summation chiefly describes FANCCβPKR binding and FANCA/FANCC/FANCG perturbations; it does not establish autonomous FANCM inhibition of PKR. The positive model location is retained as contextual relative to established nuclear repair roles, without claiming inactivity, contradiction by nuclear localization, or product equivalence. Supporting Evidence: PMID:20347429 FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions Reactome:R-HSA-9835411 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785361 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during ID2 monoubiquitination. Reason: Reactome:R-HSA-6785361 was traced to human Q8IYD8 entity or entities 6788401, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. FANCL and UBE2T perform ubiquitin transfer; FANCM is a distinct component of the DNA-associated assembly. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785361 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785732 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during nuclease recruitment. Reason: Reactome:R-HSA-6785732 was traced to human Q8IYD8 entity or entities 6788401, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. The recruited nucleases and ubiquitinated ID2 provide the downstream catalytic/recruitment activities; FANCM membership does not establish each pairwise contact. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785732 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785986 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during ICL unhooking. Reason: Reactome:R-HSA-6785986 was traced to human Q8IYD8 entity or entities 419535, 6788401, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. FAN1 and other named nucleases make the incisions; FANCM is not assigned nuclease chemistry. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785986 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786166 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during translesion synthesis. Reason: Reactome:R-HSA-6786166 was traced to human Q8IYD8 entity or entities 6788401, 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. POLN performs DNA synthesis; FANCM membership does not establish polymerase activity. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6786166 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786171 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during FANCD2 deubiquitination. Reason: Reactome:R-HSA-6786171 was traced to human Q8IYD8 entity or entities 6788401, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. USP1:WDR48 performs deubiquitination; FANCM retains a different role. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6786171 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788392 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during ATR phosphorylation. Reason: Reactome:R-HSA-6788392 was traced to human Q8IYD8 entity or entities 6788401, 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. ATR is the kinase and FANCM is among the modeled phosphorylated substrates; membership does not confer kinase activity. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6788392 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785087 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during FANCM:FAAP24/MHF association with ICL DNA. Reason: Reactome:R-HSA-6785087 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. The model assigns branchpoint recognition to FANCM, with distinct FAAP24 and MHF DNA contacts. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785087 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785126 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during FA core assembly at ICL DNA. Reason: Reactome:R-HSA-6785126 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. FANCM provides the DNA-associated recruitment context; inclusion of other core subunits is not independent DNA-binding evidence for each. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785126 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785342 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during ID2 and UBE2T recruitment. Reason: Reactome:R-HSA-6785342 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. The event assigns the cognate E2 interaction to FANCL, not to FANCM. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785342 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6785607 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during FANCMβFAAP24 association. Reason: Reactome:R-HSA-6785607 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. FANCM and FAAP24 form the explicitly modeled heterodimer. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6785607 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6786155 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during POLN recruitment. Reason: Reactome:R-HSA-6786155 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. The event describes recruitment through FANCD2/PCNA rather than an isolated FANCMβPOLN contact. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6786155 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6788385 | ACCEPT | Summary: Reactome places FANCM in nucleoplasm during ATRβATRIP recruitment. Reason: Reactome:R-HSA-6788385 was traced to human Q8IYD8 entity or entities 419535, each with its own GO:0005654 compartment and displayed-sequence coordinates 1β2048. The event names FANCM/FAAP24βRPA and FANCLβATRIP relationships; the primary contact assays were not independently reread here. The event summation was read, but its cited primary experiments were not all independently reread. These linked events share modeled participants and are not independent localization experiments; neither they nor the sequence range establish the activities of the 669- or 2022-residue products. Supporting Evidence: Reactome:R-HSA-6788385 |
| GO:0000712 resolution of meiotic recombination intermediates | IMP PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | UNDECIDED | Summary: A specific human meiotic intermediate-resolution role is not established by the inspected evidence. Reason: The QuickGO definition requires cleavage and rejoining of intermediates formed during meiotic recombination. The inspected PMID:20347428 Results demonstrate human FANCM-MHF fork remodeling, chicken DT40 mitotic sister-chromatid exchange phenotypes, and S. pombe gene conversion at blocked replication forks; these do not by themselves verify the specific human meiotic assertion. The inherited PMID:29231814 quotation establishes pachytene chromosome localization, not intermediate cleavage/rejoining. Detailed supplementary experiments were not independently read. Retain the experimental source row pending clarification rather than infer a curator error or remove it. Supporting Evidence: PMID:29231814 FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. |
| GO:0031297 replication fork processing | IMP PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: FANCM directly processes model replication forks. Reason: PMID:20347428 reconstitutes human FANCM-MHF from insect cells and demonstrates FANCM-dependent fork reversal through a four-way junction to a regressed duplex product; MHF enhances the reaction. Recruitment to nuclear ICL sites supports the cellular context. This is direct DNA-remodeling work by FANCM, not merely a loss-of-function phenotype. Full-length and engineered fragments are distinguished from natural alternative products. Supporting Evidence: PMID:20347428 MHF stimulates DNA binding and replication fork remodeling by FANCM. |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: A human FANCM pool associates with the Fanconi anaemia nuclear complex. Reason: PMID:20347428 uses nuclear-extract fractionation and reciprocal immunoprecipitation to recover FANCM with FA-core and BLM-complex components. Quantitative depletion also shows that most FANCM/MHF/FAAP24 molecules are outside that larger pool. Retain membership without making FANCM an obligatory component of every catalytic core preparation or assigning ubiquitin-ligase chemistry to it. Supporting Evidence: PMID:20347428 FANCM-MHF associates with the Fanconi anemia (FA) core complex, promotes FANCD2 monoubiquitination in response to DNA damage, and suppresses sister-chromatid exchanges. |
| GO:0071821 FANCM-MHF complex | IDA PMID:20347428 A histone-fold complex and FANCM form a conserved DNA-remode... | ACCEPT | Summary: Human FANCM forms a defined FANCM-MHF DNA-remodeling complex. Reason: PMID:20347428 identifies FANCM, MHF1/CENPS and MHF2/CENPX as the major native immunoprecipitated components and reconstitutes the three-protein complex from full-length recombinant proteins. MHF promotes FANCM DNA binding and fork reversal. Membership is distinct from the larger FA-core-associated pool. Supporting Evidence: PMID:20347428 MHF stimulates DNA binding and replication fork remodeling by FANCM. |
| GO:0003682 chromatin binding | IDA PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: Chromatin association supports FANCM chromatin binding within its DNA-remodeling assemblies. Reason: PMID:20347429 shows endogenous FANCM in the chromatin fraction and cofactor-dependent retention of FANCM and FA-core proteins. Retain the curatorβs binding interpretation in the context of the FANCM-MHF/FAAP24 machinery. Fractionation does not establish purified FANCM binding to a defined histone epitope, and no histone-specific activity is inferred. Supporting Evidence: PMID:20347429 FANCM was exclusively detected in the chromatin (P; pellet) fraction under all conditions |
| GO:0005515 protein binding | IPI PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | KEEP AS NON CORE | Summary: FANCM directly associates with CENPS/MHF1 in the tested biochemical system. Reason: PMID:20347429 Figure 4A reports purified FANCM retention with MBP-MHF1, with MBP-only and MHF2 controls. Its biochemical experiments show that MHF enhances FANCM branch migration; the independent PMID:20347428 Figure 3 and Figure 5 experiments show cooperative DNA engagement and MHF-dependent FANCM targeting. MHF1 is thus an interacting DNA-engagement cofactor in this evidence, not demonstrated cargo recruited by FANCM through chromatin-protein adaptor activity. Retain the supported interaction as non-core under the project exception; the separate complex and core-function records carry its functional context. The inherited CENPS-name quotation remains unchanged. Supporting Evidence: PMID:20347429 MHF1 has also been identified as a component of the CENPA-CAD complex and named centromere protein S (CENPS) |
| GO:0043240 Fanconi anaemia nuclear complex | IDA PMID:20347429 MHF1-MHF2, a histone-fold-containing protein complex, partic... | ACCEPT | Summary: FANCM is present in human FA-core-associated assemblies. Reason: PMID:20347429 Figure 1 and Results recover known core components with tagged FANCM and show FANCM-dependent association of MHF1 with the core. These experiments support the complex annotation while allowing distinct FANCM-MHF/FAAP24 pools. The inherited quotation concerns MHF proteins joining the assembly; FANCM membership is supported by the actual purification experiments. Supporting Evidence: PMID:20347429 These results thus identify MHF1 and MHF2 as novel components of the FA core complex. |
| GO:0062176 R-loop processing | IC PMID:26593718 The Fanconi Anemia Pathway Maintains Genome Stability by Coo... | NEW | Summary: FANCM directly contributes motor-driven R-loop disassembly. Reason: Purified human FANCM:FAAP24 displaces DNA:RNA flaps with ATP and branch-migration controls (PMID:26593718, Figure 6 and Biochemical Analysis), and disassembles telomeric R-loops on plasmids in an ATP-dependent assay (PMID:31138795, Figure 7b and In vitro R-loop resolution assays). FANCM supplies the tested motor activity, so this is participation in disassembly rather than necessity inferred only from depletion. IC records the synthesis of these experiments into the process assertion. GO:0062176 explicitly describes R-loop disassembly and lies under chromatin remodeling; it is not an ancestor or descendant of an existing process assertion here. QuickGO comparator records assign the same term to human DDX21 and DDX23 and budding-yeast Sen1; no universal exclusion of remodeling enzymes is evident. The captured GO-CAM index has no FANCM/Q8IYD8 entry. No RNA-only helicase or separate hybrid-binding function is inferred from the substrate-remodeling assays. |
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Download this section (compressed HTML)Q: How do natural 2048-, 669- and 2022-residue FANCM products differ in ATP-dependent remodeling, cofactor recruitment and cellular localization?
Q: Which branched DNA and RNA:DNA substrates are processed by FANCMβMHF versus FANCM:FAAP24 in human cells, and how are motor-dependent and recruitment-dependent functions coordinated?
Q: How do acute depletion, stable null cells and partially functional FANCM alleles differ in replication-checkpoint signaling, and what additional experiments directly test human meiotic intermediate resolution?
Experiment: Compare the separately expressed natural FANCM products with full-length wild type and explicitly engineered motor/cofactor-binding mutants in matched human-cell rescue and purified-protein assays, quantifying branch migration, R-loop displacement, chromatin recruitment and FANCD2 monoubiquitination.
Experiment: Use defined replication-fork, Holliday-junction, D-loop and RNA:DNA-flap substrates to compare FANCMβMHF and FANCM:FAAP24 preparations with ATP-hydrolysis and substrate-homology controls; connect biochemical outputs to measured noncrossover repair products.
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