Affinage

FANCM

Fanconi anemia group M protein · UniProt Q8IYD8

Length
2048 aa
Mass
232.2 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FANCM is an ATP-dependent DNA translocase and branch-point migrase that recognizes branched DNA intermediates—Holliday junctions, replication forks, and D-loops—and remodels them to preserve genome stability during replication stress (PMID:18206976, PMID:18285517). Through its N-terminal translocase domain it catalyzes bidirectional branch migration and replication fork reversal in an ATPase-dependent manner (PMID:18206976, PMID:18843105), with the Hel2i subdomain coupling specific branched-DNA engagement to catalytic migration (PMID:39189453, PMID:40447800). Beyond its enzymatic activity, FANCM serves as a chromatin-targeting scaffold that loads the Fanconi anemia core complex onto chromatin in a cell-cycle-dependent manner and is required for normal FANCD2 monoubiquitination (PMID:18174376, PMID:17289582); it bridges the FA and Bloom syndrome dissolvasome pathways through two conserved motifs—MM1 binding the core complex via FANCF and MM2 binding RMI1/topoisomerase IIIα—with loss of bridging elevating sister chromatid exchange (PMID:20064461, PMID:22392978). FANCM functions in a stable heterodimeric module with the histone-fold proteins MHF1-MHF2, which stimulate its DNA binding and fork-remodeling activity and switch its DNA-binding preference toward branched DNA (PMID:20347428, PMID:20347429, PMID:24699063), and it partners with FAAP24, whose DNA-binding (HhH)2 domain targets the complex to chromatin (PMID:17289582, PMID:24003026). Functionally distinct activities are separable: the translocase activity is dispensable for FA pathway activation but required for replication fork stability, ICL traverse, ATR/CHK1 checkpoint signaling, and recovery of stalled forks (PMID:18285517, PMID:18995830, PMID:22279085, PMID:24207054), and FANCM facilitates ATR checkpoint activation by promoting RPA and TopBP1 chromatin retention (PMID:20670894, PMID:20057355). FANCM is regulated by ATR-dependent phosphorylation at S1045 and by Plk1/β-TRCP-driven mitotic degradation that releases the core complex from chromatin (PMID:23698467, PMID:19270156). At ALT telomeres, its translocase activity and BTR-complex interaction suppress TERRA R-loops and BLM-driven break-induced telomere synthesis, rendering FANCM-BTR disruption selectively toxic to ALT cancer cells (PMID:31138795, PMID:31138797), and FANCM loss is synthetic-lethal with BRCA1 hypomorphs and with SMARCAL1 (PMID:33882298, PMID:39510066). The ortholog studies establish a conserved role in limiting recombination outcomes by dissociating D-loops, including meiotic crossover control (PMID:18851838, PMID:32386601).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2007 High

    Established that FANCM operates within a defined protein assembly and links DNA-structure recognition to the FA pathway, identifying FAAP24 as its targeting partner required for FANCD2 monoubiquitination.

    Evidence Co-IP, siRNA depletion, and cellular sensitivity assays defining the FANCM-FAAP24 interaction

    PMID:17289582

    Open questions at the time
    • Did not resolve whether FANCM itself is the catalytic translocase
    • Mechanism of structure recognition unresolved at this stage
  2. 2008 High

    Defined the core biochemical activity of FANCM by showing it is an ATP-dependent branch-point migrase and fork-reversal enzyme acting directly on branched DNA, separating this enzymatic role from its requirement for FANCD2 monoubiquitination.

    Evidence In vitro reconstitution with purified protein, ATPase/Walker-B-defective mutants, branch migration and fork reversal assays, siRNA complementation

    PMID:18206976 PMID:18285517 PMID:18843105

    Open questions at the time
    • How translocase activity contributes in vivo not yet shown
    • Substrate selectivity determinants within the protein unmapped
  3. 2008 High

    Showed FANCM is a chromatin-localized scaffold whose recruitment, together with FAAP24, is required to load the FA core complex onto chromatin, and that it also feeds ATR/CHK1 checkpoint signaling via HCLK2 independently of the core complex.

    Evidence Chromatin fractionation, siRNA depletion, immunofluorescence, Co-IP, and translocase-dead mutant analysis

    PMID:18174376 PMID:18995830

    Open questions at the time
    • Precise determinants of cell-cycle-regulated chromatin loading unresolved
    • How translocase activity drives checkpoint signaling mechanistically unclear
  4. 2008 High

    Demonstrated through the fission yeast ortholog Fml1 that the branch-migration/D-loop-disruption activity is evolutionarily conserved and channels stalled-fork repair toward Rad51-dependent gene conversion while limiting crossovers.

    Evidence Genetic epistasis in S. pombe and in vitro D-loop disruption and fork reversal assays

    PMID:18851838

    Open questions at the time
    • Conservation of crossover-limiting function in vertebrates not addressed here
  5. 2009 High

    Revealed how FANCM is regulated across the cell cycle and the replication-stress response, showing mitotic Plk1/β-TRCP degradation releases the core complex and that Chk1 signaling stabilizes FANCM in a feedback loop while it controls fork elongation.

    Evidence Non-degradable and ATPase-defective mutants, chromatin fractionation, DNA fiber analysis, proteasome inhibition, and Xenopus extract phosphorylation studies

    PMID:19270156 PMID:19465393 PMID:19633289 PMID:20010692

    Open questions at the time
    • Phosphosites driving degradation not fully mapped
    • Walker-B mutant SCE phenotype mechanism beyond BLM epistasis incomplete
  6. 2010 High

    Established FANCM as a constitutive partner of the histone-fold heterodimer MHF1-MHF2, which stimulates its DNA binding and fork remodeling and is needed for FANCD2 monoubiquitination and suppression of chromosomal instability.

    Evidence Biochemical reconstitution, ChIP, siRNA/knockout, branch migration assays, and FANCD2 monoubiquitination readouts

    PMID:20347428 PMID:20347429

    Open questions at the time
    • Structural basis of MHF stimulation not yet resolved at this point
  7. 2010 High

    Defined how FANCM/FAAP24 couples to checkpoint activation, showing it recruits RPA and retains TopBP1 at ICL-stalled forks to enable ATR phosphorylation of CHK1 and SMC1, with RPA recruitment dependent on FAAP24 DNA binding rather than FANCM translocase.

    Evidence siRNA depletion, separation-of-function mutants (translocase vs DNA-binding), foci analysis, chromatin fractionation, and ATR substrate readouts in DT40

    PMID:20057355 PMID:20670894

    Open questions at the time
    • How TopBP1 retention is physically achieved unresolved
    • Order of RPA, TopBP1, and core-complex recruitment events not fully ordered
  8. 2012 High

    Provided the structural logic for FANCM's pathway-bridging and DNA-remodeling scaffolds by solving the MHF-FANCM and RMI-FANCM interfaces and linking their disruption to elevated SCE and altered localization.

    Evidence X-ray crystallography of MHF1-MHF2-FANCM and RMI core-FANCM peptide complexes with mutagenesis and SCE assays

    PMID:20064461 PMID:22392978 PMID:22510687

    Open questions at the time
    • Full-length architecture coupling these modules to the translocase not resolved
  9. 2012 High

    Separated the FANCM repair functions in vivo, showing translocase activity is essential for fork stability and that its loss converts stalled forks into DSBs that trigger ATM-CtIP-dependent resection and HR.

    Evidence Translocase-dead knock-in, DNA fiber analysis, ATM activation assays, and genetic epistasis

    PMID:22279085

    Open questions at the time
    • Direct demonstration of fork reversal as the protective mechanism in cells still pending
  10. 2013 High

    Resolved the FANCM-FAAP24 C-terminal architecture and demonstrated that FANCM mediates replication traverse of ICLs, allowing forks to bypass crosslinks without repair, using both translocase and DNA-binding activities.

    Evidence Crystallography and EM of the FANCM-FAAP24 CTD with DNA, single-molecule ICL-traverse imaging in living cells, and separation-of-function mutants

    PMID:23333308 PMID:23932590 PMID:24003026 PMID:24207054

    Open questions at the time
    • FANCM nuclease domain is catalytically dead—its structural role remains functional but non-enzymatic
    • How traverse is coordinated with later repair unresolved
  11. 2013 High

    Identified ATR-FANCM feedback through phosphorylation at S1045, required for FA pathway integrity, ICL-site recruitment, and checkpoint enforcement, establishing post-translational control of FANCM during genotoxic stress.

    Evidence Phospho-specific antibody, ATR inhibition, and S1045A mutant with checkpoint readouts

    PMID:23698467

    Open questions at the time
    • Whether S1045 phosphorylation directly alters translocase or scaffolding activity not resolved
  12. 2014 High

    Showed the FANCM MID switches MHF DNA-binding preference from duplex to branched DNA via a zinc-stabilized interface, defining a structural mechanism coupling complex assembly to substrate specificity and FA network activation.

    Evidence Crystallography of MHF-MID, structure-guided mutagenesis, DNA binding and FANCD2 monoubiquitination assays

    PMID:24699063

    Open questions at the time
    • In vivo consequence of the binding-mode switch on specific substrates incomplete
  13. 2016 High

    Connected FANCM directly to the replisome and ICL recognition, showing a stress-stimulated PIP-box interaction with PCNA and a translocase/BTR/ATR-dependent recruitment pathway to ICL-stalled forks that drives hyperphosphorylation and ICL traverse independently of the core complex.

    Evidence PIP-box mutant analysis, recruitment assays, Co-IP, and epistasis with BLM, ATR, and FAAP24

    PMID:26825464 PMID:28058110

    Open questions at the time
    • Hierarchy of PCNA, BTR, and FAAP24 contributions to recruitment not fully ordered
  14. 2017 High

    Extended FANCM function to telomere maintenance, showing it is recruited to ALT telomeres under replication stress and that its loss provokes BRCA1/BLM-dependent resection and HR to resolve telomeric replication stress.

    Evidence siRNA depletion, telomere-specific SMARD, co-depletion epistasis, and immunofluorescence

    PMID:28673972

    Open questions at the time
    • Direct biochemical substrate at ALT telomeres not yet defined at this stage
  15. 2019 High

    Defined the mechanism of FANCM at ALT telomeres as translocase-dependent suppression of TERRA R-loops and BLM-driven break-induced telomere synthesis via BTR-complex interaction, revealing FANCM-BTR disruption as selectively toxic to ALT cancers.

    Evidence In vitro R-loop unwinding, translocase-dead and BTR-interaction mutants, C-circle and break-induced replication assays, and RNase H1 rescue across three independent labs

    PMID:31138795 PMID:31138797 PMID:31836759

    Open questions at the time
    • Whether R-loop unwinding is the sole protective activity at telomeres not fully isolated
    • Therapeutic window of FANCM-BTR disruption in vivo unaddressed
  16. 2019 High

    Showed FANCM remodels the stalled replisome after ICL encounter, binding the replisome in an ATR/FANCD2-dependent manner and triggering GINS release from CMG, linking FANCM phosphorylation to active replisome restructuring.

    Evidence Proximity ligation and Co-IP with replisome components, GINS-release assay, and ATR inhibition

    PMID:31067464

    Open questions at the time
    • Direct enzymatic basis for GINS release not established
    • Fate of the remodeled replisome unresolved
  17. 2021 High

    Demonstrated that FANCM repair functions partition among molecularly separable scaffolding domains while ATPase activity is universally required, and that FANCM loss or ATPase inactivation is synthetic-lethal with BRCA1 hypomorphs, defining therapeutic vulnerability.

    Evidence Endogenous domain-specific Fancm mutations in mouse ES cells, repair assays, and synthetic-lethality testing

    PMID:33882298

    Open questions at the time
    • Molecular trigger of FANCM trapping at forks upon ATPase inactivation unresolved
  18. 2022 High

    Identified And-1 as a replisome sensor of ICL-stalled forks that recruits FANCM/FAAP24 via ATR-induced phosphorylation, placing FANCM recruitment downstream of a defined replisome-resident signal.

    Evidence Co-IP, phospho-specific antibody, And-1 T826A mutant, chromatin recruitment, and FANCD2 monoubiquitination assays

    PMID:35867033

    Open questions at the time
    • Whether And-1 and PCNA recruitment routes are redundant or sequential unresolved
  19. 2024 High

    Pinned down the structural and catalytic basis of FANCM's two activities, showing the Hel2i subdomain mediates branched-DNA engagement and ATP-dependent migration, while the C-terminal branched-DNA-binding mode enhances FANCD2-FANCI monoubiquitination through FA core complex interaction.

    Evidence Atomic-resolution crystal structures of N-terminal translocase and C-terminal FAAP24-bound regions with branched DNA, Hel2i mutagenesis, biochemical reconstitution, and ALT/monoubiquitination rescue assays

    PMID:39189453 PMID:40447800

    Open questions at the time
    • Full-length conformational coupling between the two domains during catalysis not yet captured
  20. 2024 High

    Expanded the genome-protective network of FANCM, revealing synthetic lethality with SMARCAL1 at replication-challenging repeats and a core-complex-independent role in suppressing 53BP1/PRIMPOL-driven ssDNA gaps that confers PARP inhibitor resistance.

    Evidence CRISPR synthetic-lethality screen with double knockouts, ssDNA gap and resection assays, and genetic epistasis with 53BP1 and PRIMPOL

    PMID:38985669 PMID:39510066

    Open questions at the time
    • Mechanism by which FANCM counteracts 53BP1 at gaps unresolved
    • Whether translocase activity is required for gap suppression not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FANCM's separable enzymatic and scaffolding activities are dynamically switched and coordinated in real time across distinct genomic contexts (forks, ICLs, ALT telomeres, fragile sites) by phosphorylation, partner binding, and conformational change remains unresolved.
  • No unified model linking domain coupling to context-specific output
  • Full-length structure during catalysis not determined
  • Regulatory integration of ATR phosphorylation with degradation and recruitment incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0140657 ATP-dependent activity 6 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140097 catalytic activity, acting on DNA 3
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-73894 DNA Repair 5 R-HSA-69306 DNA Replication 4 R-HSA-8953897 Cellular responses to stimuli 4
Partners
AND-1BLMFAAP24FANCFMHF1MHF2PCNARMI1
Complex memberships
BLM-TOP3A-RMI (BTR) dissolvasomeFANCM-FAAP24FANCM-MHF1-MHF2Fanconi anemia core complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 FANCM associates with FAAP24 through its C-terminal region; FAAP24 shares homology with XPF family flap/fork endonucleases and targets FANCM to DNA structures mimicking replication/repair intermediates. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. Co-immunoprecipitation, siRNA depletion, cellular sensitivity assays Molecular cell High 17289582
2008 Purified FANCM binds Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner; FANCM can dissociate large recombination intermediates via branch migration of Holliday junctions through 2.6 kb of DNA. In vitro branch migration assay with purified protein, ATPase-defective mutant analysis Molecular cell High 18206976
2008 FANCM promotes reversal of model replication forks via concerted displacement and annealing of nascent and parental DNA strands (fork reversal); this activity also occurs when the lagging strand template is partially single-stranded and bound by RPA. In vitro fork reversal assay with purified FANCM, biochemical reconstitution Proceedings of the National Academy of Sciences of the United States of America High 18843105
2008 FANCM possesses ATP-independent DNA binding activity and ATP-dependent bi-directional branch-point translocation on four-way junction DNA. ATP-dependent activities are required for cellular resistance to mitomycin C but not for monoubiquitination of FANCD2/FANCI; the entire helicase domain (ATP-dependent and independent) is required for monoubiquitination. siRNA complementation, in vitro DNA binding and branch migration assays, mutant analysis Human molecular genetics High 18285517
2008 FANCM and FAAP24 are required for cell-cycle-dependent chromatin loading of the FA core complex; FANCM is exclusively localized to chromatin and undergoes cell-cycle-dependent phosphorylation. Depletion of FAAP24 disrupts chromatin association of FANCM and destabilizes it, preventing FA core complex recruitment to chromatin. Chromatin fractionation, siRNA depletion, immunofluorescence, co-immunoprecipitation Blood High 18174376
2008 FANCM and FAAP24 interact with checkpoint protein HCLK2 independently of the FA core complex. Downregulation of FANCM or FAAP24 compromises ATR/Chk1-mediated checkpoint signaling. The DNA translocase activity of FANCM—dispensable for FA pathway activation—is required for its role in ATR/Chk1 signaling. Co-immunoprecipitation, siRNA depletion, phosphorylation assays, checkpoint marker analysis Molecular cell High 18995830
2008 The FANCM ortholog Fml1 in fission yeast promotes Rad51-dependent gene conversion at stalled/blocked replication forks and limits crossing over during mitotic double-strand break repair; in vitro Fml1 catalyzes both replication fork reversal and D-loop disruption. Genetic epistasis in S. pombe, in vitro D-loop disruption and fork reversal assays Molecular cell High 18851838
2009 FANCM connects the FA and Bloom Syndrome pathways via two conserved interaction motifs: MM1 interacts with the FA core complex by binding FANCF, and MM2 interacts with RMI1 and topoisomerase IIIα (components of the BLM/BS dissolvasome complex). Both motifs are independently required to activate their respective pathways, and loss of this bridging causes elevated sister chromatid exchanges. Mutant interaction motif analysis, co-immunoprecipitation, sister chromatid exchange assays Molecular cell High 20064461
2009 FANCM is hyperphosphorylated and degraded during mitosis; β-TRCP and Plk1 are the key regulators of FANCM degradation. Non-degradable FANCM mutants retain the FA core complex in chromatin and disrupt the FA pathway, revealing a mechanism for cell-cycle-dependent regulation. Co-immunoprecipitation, dominant-negative/non-degradable mutant analysis, chromatin fractionation Genes & development High 19270156
2009 In Xenopus egg extracts, xFANCM binds chromatin in a replication-dependent manner and is phosphorylated in response to DNA damage; chromatin binding and phosphorylation are mediated in part by FANCD2 and by checkpoint kinases ATR and ATM. Xenopus egg extract system, chromatin fractionation, immunodepletion, kinase inhibitor experiments The Journal of biological chemistry Medium 19633289
2009 FANCM controls DNA chain elongation in an ATPase-dependent manner in vivo; in the presence of replication inhibitors that do not damage DNA, FANCM counteracts fork movement, whereas through damaged DNA FANCM promotes replication and recovers stalled forks. Chk1 signaling prevents FANCM degradation by the proteasome after DNA damage, and FANCM stabilizes Chk1 in a feedback loop. DNA fiber analysis, ATPase-defective mutant, siRNA depletion, proteasome inhibitor experiments The EMBO journal Medium 20010692
2010 FANCM forms a conserved DNA-remodeling complex with the histone-fold heterodimer MHF1-MHF2; MHF stimulates DNA binding and replication fork remodeling by FANCM. FANCM and MHF are rapidly recruited to forks stalled by DNA interstrand crosslinks and are required for cellular resistance. In vertebrates, FANCM-MHF promotes FANCD2 monoubiquitination and suppresses sister chromatid exchanges. Biochemical reconstitution, chromatin immunoprecipitation, siRNA/knockout, FANCD2 monoubiquitination assay Molecular cell High 20347428 20347429
2010 MHF1 and MHF2 assemble into a heterodimer that binds DNA and enhances the DNA branch migration activity of FANCM; suppression of MHF1 destabilizes FANCM and MHF2, impairs FANCD2 monoubiquitination and foci formation, disrupts chromatin localization of FA core complex proteins, and causes chromosomal instability. siRNA depletion, co-immunoprecipitation, DNA binding assay, branch migration assay Molecular cell High 20347429
2010 FANCM and FAAP24 are specifically required for recruitment of RPA to ICL-stalled replication forks; ICL-induced RPA foci formation requires the DNA-binding activity of FAAP24 but not the DNA translocase activity of FANCM; FANCM/FAAP24-dependent RPA recruitment is required for efficient ATR-mediated checkpoint activation in response to ICL. siRNA depletion, immunofluorescence foci analysis, translocase-dead mutant, ATR substrate phosphorylation assay Molecular cell High 20670894
2010 FANCM promotes replication fork restart and limits accumulation of RPA-ssDNA; in DT40 cells this process is controlled by ATR and PLK1. FANCM promotes chromatin retention of TopBP1, and failure to retain TopBP1 impairs ATR phosphorylation of downstream targets including Chk1 and SMC1. DT40 knockout, DNA fiber analysis, chromatin fractionation, epistasis with ATR/PLK1 inhibitors The EMBO journal High 20057355
2012 Crystal structures of MHF1-MHF2 alone and bound to FANCM fragment (residues 661-800) show MHF forms a compact tetramer; FANCM binds through a 'dual-V' shaped structure; FANCM and (MHF1-MHF2)2 cooperate to form a new DNA-binding site coupled to the canonical L1L2 region. A disease-associated FANCM mutant alters the MHF-FANCM interaction and subcellular localization. X-ray crystallography, mutagenesis, subcellular localization assay Nature communications High 22510687
2012 The X-ray crystal structure of the RMI core complex bound to a conserved FANCM peptide shows FANCM binds both RMI1 and RMI2 through a hydrophobic 'knobs-into-holes' arrangement. Alanine substitutions at key interface residues strongly destabilize the complex and increase SCE levels comparable to BLM- or FANCM-deficient cells. X-ray crystallography, mutagenesis, co-immunoprecipitation, sister chromatid exchange assay Proceedings of the National Academy of Sciences of the United States of America High 22392978
2012 FANCM translocase activity is essential for promoting replication fork stability; cells expressing translocase-defective FANCM show increased stalled forks that degenerate into DSBs leading to ATM activation, CtIP-dependent end resection, and homologous recombination repair. Translocase-dead mutant knock-in, DNA fiber analysis, ATM activation assays, genetic epistasis with ATM/CtIP Human molecular genetics High 22279085
2013 FANCM/MHF complex translocase and DNA-binding activities promote replication traverse of DNA interstrand crosslinks, allowing DNA synthesis to continue past ICLs without lesion repair; inactivation of translocase or DNA-binding activities strongly reduces traverse frequency. Single-molecule visualization of replication fork encounters with ICLs in living cells, translocase-dead and DNA-binding mutants Molecular cell High 24207054
2013 FANCM and FAAP24 possess non-overlapping functions: FAAP24 promotes ATR-mediated checkpoint activation in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent ICL repair by facilitating recruitment of lesion incision activities requiring its translocase activity. Isogenic FANCM and FAAP24 knockout cell lines, epistasis analysis, DNA repair assays Molecular cell High 23333308
2013 Crystal structure of the C-terminal segment of FANCM in complex with FAAP24 reveals both proteins have a nuclease domain and tandem helix-hairpin-helix (HhH)2 domain; variations in key residues render FANCM's nuclease domain catalytically inactive; the first HhH motif of FAAP24 is a DNA-binding site critical for targeting FANCM-FAAP24 to chromatin. X-ray crystallography, mutagenesis, chromatin-targeting assay Nucleic acids research High 24003026
2013 Structure of FANCM C-terminal domain (FANCMCTD) bound to FAAP24 and DNA reveals the FANCM (HhH)2 domain is buried while FAAP24 (HhH)2 domain engages DNA; a second DNA contact and metal center in the FANCM pseudo-nuclease domain are required for double-stranded DNA binding in vitro and FANCM-FAAP24 function in vivo. EM shows the translocase domain lies in proximity to FANCMCTD. X-ray crystallography, electron microscopy, mutagenesis, in vitro DNA binding, in vivo complementation Structure High 23932590
2013 ATR-dependent phosphorylation of FANCM at serine 1045 in response to genotoxic stress is required for FANCM functions including FA pathway integrity, recruitment of FANCM to ICL sites, preventing premature mitotic entry, and efficient CHK1 and G2/M checkpoint activation, establishing an ATR-FANCM feedback loop. Phospho-specific antibody, ATR inhibition, phosphorylation-defective mutant (S1045A), checkpoint activation assays Cancer research High 23698467
2014 Crystal structure of MHF bound to the MHF-interaction domain (MID) of FANCM shows one MHF heterotetramer wrapped by a single MID polypeptide; a zinc atom-liganding structure at the interface stabilizes the complex; MID binding switches MHF DNA-binding preference from duplex DNA to branched DNA. Mutations disrupting the composite DNA-binding surface or protein-protein interface impair FA network activation and genome stability. X-ray crystallography, structure-guided mutagenesis, DNA binding assays, FANCD2 monoubiquitination assay Cell research High 24699063
2016 FANCM interacts with PCNA through a conserved PIP-box motif; the interaction is strongly stimulated by replication stress. A PIP-box mutant FANCM variant is defective in promoting replication traverse of ICLs and inefficient in promoting FANCD2 monoubiquitination. Co-immunoprecipitation, PIP-box mutant analysis, ICL traverse assay, FANCD2 monoubiquitination assay, structural analysis of archaeal Hef-PCNA interaction Nucleic acids research High 26825464
2016 FANCM recruitment to ICL-stalled replication forks depends on its intrinsic DNA translocase activity, FAAP24 DNA-binding, ATR kinase activity, and direct interaction with the BLM-TOP3A-RMI (BTR) complex including the helicase activity of BLM; this recruitment is independent of the FA core complex and FANCD2-FANCI. The FANCM-BLM interaction is critical for FANCM hyperphosphorylation, FA pathway activation, and ICL traverse. Novel FANCM-recruitment protocol, translocase-dead and interaction mutants, co-immunoprecipitation, epistasis analysis Cell discovery High 28058110
2017 FANCM depletion induces replication stress primarily at telomeres of ALT cells; FANCM, BRCA1, and BLM are actively recruited to ALT telomeres experiencing replication stress; BRCA1 and BLM recruitment is interdependent and regulated by ATR and Chk1. In FANCM-depleted ALT cells, BRCA1 and BLM resolve telomeric replication stress by stimulating DNA end resection and homologous recombination. siRNA depletion, telomere-specific single-molecule analysis of replicated DNA (SMARD), co-depletion epistasis, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 28673972
2019 The ATPase/translocase activity of FANCM keeps telomeric replicative stress in check in ALT cells by suppressing BLM-driven telomere stress and by unwinding telomeric R-loops (TERRA R-loops) in vitro; FANCM depletion increases ALT-associated marks, de novo telomeric DNA synthesis, and BLM-dependent telomere dysfunction. RNaseH1 overexpression abrogates residual replication stress in FANCM+BLM co-depleted cells. siRNA/shRNA depletion, in vitro R-loop unwinding assay, ALT biomarker analysis, epistasis with BLM depletion and RNaseH1 overexpression Nature communications High 31138795
2019 FANCM-mediated attenuation of ALT requires its DNA translocase activity and interaction with the BTR (BLM-TOP3A-RMI) complex but does not require the FA core complex. FANCM depletion provokes ALT activity via increased break-induced telomere synthesis. Synthetic inhibition of FANCM-BTR complex formation is selectively toxic to ALT cancer cells. siRNA/shRNA depletion, translocase-dead mutant, BTR interaction mutant, break-induced replication assay, ALT biomarker analysis Nature communications High 31138797
2019 FANCM (via FAAP24 interaction) disrupts TERRA R-loops at ALT telomeres; depletion of FAAP24 or FANCM induces dramatic increase of C-circle formation driven by ATR/Chk1, BTR complex, HR proteins (BRCA2, PALB2, RAD51), and BIR factors (POLD1, POLD3). RNase H1 overexpression attenuates ALT phenotypes caused by FANCM deficiency. siRNA depletion of FANCM complex components, C-circle assay, co-depletion epistasis, RNaseH1 overexpression Scientific reports High 31836759
2019 FANCM binds the replisome complex following ICL introduction in an ATR- and FANCD2-dependent but FA core protein- and FAAP24-independent manner, with concomitant release of GINS proteins from the CMG helicase. ATR-dependent phosphorylated FANCM promotes this replisome remodeling. Proximity ligation and co-immunoprecipitation with replisome components, GINS release assay, ATR inhibition, in situ replisome analysis Cell reports High 31067464
2021 Distinct FANCM repair functions at stalled forks are enacted by molecularly separable scaffolding domains; FANCM ATPase function is required for all its repair functions and its inactivation 'traps' FANCM at stalled forks. Brca1 hypomorphic mutants are synthetic lethal with Fancm null or Fancm ATPase-defective mutants. Endogenous Fancm domain-specific mutations in mouse ES cells, DNA repair assays, synthetic lethality analysis Molecular cell High 33882298
2022 And-1 (a replisome protein) is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs; this requires ATR-induced phosphorylation of And-1 at T826, which triggers an intramolecular change promoting And-1 interaction with FANCM/FAAP24. Co-immunoprecipitation, phospho-specific antibody, phospho-dead mutant (T826A), FANCD2 monoubiquitination assay, chromatin recruitment assay Cancer research High 35867033
2024 The Hel2i subdomain within the N-terminal translocase domain is crucial for FANCM's specific branched DNA engagement, coupling DNA binding to catalytic ATP-dependent branch migration. Mutations in Hel2i or key DNA-binding residues diminish junction DNA affinity and abolish branch migration activity, and these mutants fail to rescue ALT cell death or telomere replication stress upon FANCM depletion. Mutagenesis of Hel2i subdomain, DNA binding assays, branch migration assay, ALT cell rescue assay, cell cycle and telomere stress assays Nucleic acids research High 39189453
2024 Crystal structures of FANCM's N-terminal translocase domain (2.2 Å) and C-terminal FAAP24-bound region (2.4 Å), both complexed with branched DNA, reveal two distinct mechanisms: (1) ATP-dependent branch migration essential for DNA damage survival, and (2) a branched DNA-binding mode at the C-terminal domain that enhances FANCD2-FANCI monoubiquitination through FA core complex interaction. X-ray crystallography, biochemical reconstitution, mutagenesis, FANCD2-FANCI monoubiquitination assay, cellular rescue experiments The EMBO journal High 40447800
2024 SMARCAL1 displays a profound synthetic-lethal interaction with FANCM; combined loss causes severe genome instability linked to chromosome breakage at simple repeat loci that challenge replication fork progression. CRISPR-based synthetic lethality screen, double-knockout cell lines, genomic instability assays Molecular cell High 39510066
2024 FANCM promotes PARP inhibitor resistance independent of the FA core complex by minimizing ssDNA gap formation behind replication forks through counteracting 53BP1; FANCM depletion leads to increased ssDNA gaps (via 53BP1- and PRIMPOL-dependent mechanisms) and reduced resection of collapsed forks, while 53BP1 deletion restores resection and mitigates PARPi sensitivity. siRNA depletion, ssDNA gap assay, genetic epistasis with 53BP1 and PRIMPOL, DNA fiber analysis, resection assay Cell reports High 38985669
2009 Walker B motif mutation in avian FANCM (DT40 cells) does not affect FA pathway activation or crosslink repair, but results in elevated sister chromatid exchanges; FANCM functions with BLM helicase to suppress spontaneous SCE events, placing them in the same pathway. DT40 knockout complementation with Walker B mutant, sister chromatid exchange assay, epistasis with BLM Nucleic acids research High 19465393
2018 FANCM, along with FAAP24 and MHF1/2, is recruited to CFS-derived structure-prone AT-rich sequences and suppresses DSB formation and mitotic recombination there in a manner dependent on FANCM translocase activity; this function is independent of the FA core complex and FANCI-FANCD2 complex. FANCM knockout, translocase-dead mutant, DSB assays at AT-rich sequences, epistasis with FA complex components Nature communications High 30022024
2018 In C. elegans, FANCM/CeFNCM-1 interacts with the histone demethylase LSD1/CeSPR-5; LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation; FANCM relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5. The FA pathway is required for H3K4me2 maintenance. Co-immunoprecipitation, fluorescence microscopy, genetic epistasis in C. elegans Genetics Medium 29588287
2020 In budding yeast, Mph1 (FANCM ortholog) prevents precocious DSB strand exchange between sister chromatids before homologs complete pairing by dissociating precocious D-loops between sister chromatids; this ensures high levels of crossovers and non-crossovers between homologs. Later recombination events are protected from Mph1-mediated dissociation by synapsis protein Zip1. Yeast genetics, D-loop dissociation assay, meiotic recombination analysis, Zip1 epistasis Developmental cell High 32386601

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Molecular cell 250 17289582
2012 FANCM limits meiotic crossovers. Science (New York, N.Y.) 223 22723424
2008 The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. Molecular cell 215 18206976
2009 FANCM connects the genome instability disorders Bloom's Syndrome and Fanconi Anemia. Molecular cell 212 20064461
2008 Remodeling of DNA replication structures by the branch point translocase FANCM. Proceedings of the National Academy of Sciences of the United States of America 197 18843105
2010 A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Molecular cell 192 20347428
2019 FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops. Nature communications 188 31138795
2008 FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Molecular cell 167 18995830
2010 MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Molecular cell 166 20347429
2019 The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT). Nature communications 164 31138797
2013 The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Molecular cell 164 24207054
2008 Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 154 18174376
2014 Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America 149 25288723
2008 The FANCM ortholog Fml1 promotes recombination at stalled replication forks and limits crossing over during DNA double-strand break repair. Molecular cell 135 18851838
2015 Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM. Proceedings of the National Academy of Sciences of the United States of America 132 25825745
2010 ATR activation and replication fork restart are defective in FANCM-deficient cells. The EMBO journal 130 20057355
2015 AAA-ATPase FIDGETIN-LIKE 1 and Helicase FANCM Antagonize Meiotic Crossovers by Distinct Mechanisms. PLoS genetics 127 26161528
2017 FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres. Proceedings of the National Academy of Sciences of the United States of America 125 28673972
2019 FANCM suppresses DNA replication stress at ALT telomeres by disrupting TERRA R-loops. Scientific reports 111 31836759
2010 The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Molecular cell 105 20670894
2008 FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair. Human molecular genetics 99 18285517
2018 Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia. American journal of human genetics 96 30075111
2012 The fission yeast FANCM ortholog directs non-crossover recombination during meiosis. Science (New York, N.Y.) 93 22723423
2010 The FANCM family of DNA helicases/translocases. DNA repair 92 20117061
2015 FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor. Human molecular genetics 84 26130695
2014 FANCM-associated proteins MHF1 and MHF2, but not the other Fanconi anemia factors, limit meiotic crossovers. Nucleic acids research 84 25038251
2018 A homozygous FANCM frameshift pathogenic variant causes male infertility. Genetics in medicine : official journal of the American College of Medical Genetics 81 29895858
2017 Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. JAMA oncology 76 28033443
2009 FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling. The EMBO journal 76 20010692
2015 Functions and regulation of the multitasking FANCM family of DNA motor proteins. Genes & development 75 26341555
2017 Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. Genetics in medicine : official journal of the American College of Medical Genetics 74 28837162
2012 The DNA translocase activity of FANCM protects stalled replication forks. Human molecular genetics 71 22279085
2009 The Walker B motif in avian FANCM is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair. Nucleic acids research 70 19465393
2013 FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Molecular cell 69 23333308
2017 Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia. Genetics in medicine : official journal of the American College of Medical Genetics 67 28837157
2017 A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency. eLife 63 29231814
2021 FANCM regulates repair pathway choice at stalled replication forks. Molecular cell 60 33882298
2009 Regulated degradation of FANCM in the Fanconi anemia pathway during mitosis. Genes & development 60 19270156
2012 The structure of the FANCM-MHF complex reveals physical features for functional assembly. Nature communications 58 22510687
2018 The concerted roles of FANCM and Rad52 in the protection of common fragile sites. Nature communications 55 30022024
2012 Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome. Proceedings of the National Academy of Sciences of the United States of America 53 22392978
2010 The archaeal Xpf/Mus81/FANCM homolog Hef and the Holliday junction resolvase Hjc define alternative pathways that are essential for cell viability in Haloferax volcanii. DNA repair 53 20667794
2013 ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer research 52 23698467
2019 The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. International journal of cancer 51 30426508
2019 Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2. Cell reports 50 31067464
2016 Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks. Cell discovery 50 28058110
2017 Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene. Oncotarget 47 28881617
2016 FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks. Nucleic acids research 44 26825464
2019 The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. NPJ breast cancer 39 31700994
2009 The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways. The Journal of biological chemistry 38 19633289
2018 FANCM Limits Meiotic Crossovers in Brassica Crops. Frontiers in plant science 37 29628933
2012 The Fanconi anaemia components UBE2T and FANCM are functionally linked to nucleotide excision repair. PloS one 37 22615860
2020 DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain. Nature communications 36 32769987
2014 DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity. DNA repair 34 25583207
2017 FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population. Breast cancer research and treatment 33 28702895
2022 FANCM promotes class I interfering crossovers and suppresses class II non-interfering crossovers in wheat meiosis. Nature communications 31 35752733
2020 DNA Helicase Mph1FANCM Ensures Meiotic Recombination between Parental Chromosomes by Dissociating Precocious Displacement Loops. Developmental cell 30 32386601
2019 ALT control, delete: FANCM as an anti-cancer target in Alternative Lengthening of Telomeres. Nucleus (Austin, Tex.) 30 31663812
2012 Rad5-dependent DNA repair functions of the Saccharomyces cerevisiae FANCM protein homolog Mph1. The Journal of biological chemistry 29 22696213
2009 Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition. Carcinogenesis 28 19737859
2013 Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex. Structure (London, England : 1993) 27 23932590
2019 A tumor suppressive DNA translocase named FANCM. Critical reviews in biochemistry and molecular biology 25 30714416
2011 Human MutS and FANCM complexes function as redundant DNA damage sensors in the Fanconi Anemia pathway. DNA repair 25 21975120
2009 FANCM-FAAP24 and FANCJ: FA proteins that metabolize DNA. Mutation research 25 19379763
2014 MHF1 plays Fanconi anaemia complementation group M protein (FANCM)-dependent and FANCM-independent roles in DNA repair and homologous recombination in plants. The Plant journal : for cell and molecular biology 24 24635147
2010 The involvement of FANCM, FANCI, and checkpoint proteins in the interstrand DNA crosslink repair pathway is conserved in C. elegans. DNA repair 24 20075016
2019 FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer. Cancer genetics 23 31078449
2013 Intracellular dynamics of archaeal FANCM homologue Hef in response to halted DNA replication. Nucleic acids research 22 24049073
2018 FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine. BMC medical genetics 21 29351780
2014 The histone-fold complex MHF is remodeled by FANCM to recognize branched DNA and protect genome stability. Cell research 21 24699063
2019 ALTernative Functions for Human FANCM at Telomeres. Frontiers in molecular biosciences 20 31552268
2018 A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy. Breast (Edinburgh, Scotland) 20 29287190
2014 Drosophila FANCM helicase prevents spontaneous mitotic crossovers generated by the MUS81 and SLX1 nucleases. Genetics 19 25205745
2022 And-1 Coordinates with the FANCM Complex to Regulate Fanconi Anemia Signaling and Cisplatin Resistance. Cancer research 17 35867033
2021 Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia. Frontiers in genetics 16 34976027
2021 Fanconi anemia ortholog FANCM regulates meiotic crossover distribution in plants. Plant physiology 15 33576801
2018 Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 Are Required for Maintaining Histone Methylation Levels and Interact with the Histone Demethylase LSD1/SPR-5 in Caenorhabditis elegans. Genetics 15 29588287
2013 Structural insights into the functions of the FANCM-FAAP24 complex in DNA repair. Nucleic acids research 15 24003026
2024 FANCM branchpoint translocase: Master of traverse, reverse and adverse DNA repair. DNA repair 14 38878565
2021 Protein truncating variants in FANCM and risk for ER-negative/triple negative breast cancer. NPJ breast cancer 14 34584094
2016 FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome. International journal of cancer 14 27542569
2013 Middle region of FancM interacts with Mhf and Rmi1 in silkworms, a species lacking the Fanconi anaemia (FA) core complex. Insect molecular biology 14 24286570
2023 FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European journal of human genetics : EJHG 13 36707629
2009 FANCM-FAAP24 and HCLK2: roles in ATR signalling and the Fanconi anemia pathway. Cell cycle (Georgetown, Tex.) 13 19282663
2024 Profound synthetic lethality between SMARCAL1 and FANCM. Molecular cell 12 39510066
2020 Improved Genome Editing through Inhibition of FANCM and Members of the BTR Dissolvase Complex. Molecular therapy : the journal of the American Society of Gene Therapy 12 33678249
2023 Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals. Cell genomics 11 37601968
2020 The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases. Cancers 10 31991861
2024 FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition. Cell reports 9 38985669
2016 miR146a-mediated targeting of FANCM during inflammation compromises genome integrity. Oncotarget 9 27351285
2022 Division of Labor by the HELQ, BLM, and FANCM Helicases during Homologous Recombination Repair in Drosophila melanogaster. Genes 8 35328029
2020 FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor. Molecular genetics & genomic medicine 8 33118316
2024 Mechanism of structure-specific DNA binding by the FANCM branchpoint translocase. Nucleic acids research 7 39189453
2021 Fanconi-like anemia related to a FANCM mutation. European journal of medical genetics 7 34793962
2019 Correction: A homozygous FANCM frameshift pathogenic variant causes male infertility. Genetics in medicine : official journal of the American College of Medical Genetics 7 30158692
2009 FANCM: A landing pad for the Fanconi Anemia and Bloom's Syndrome complexes. Molecular cell 7 20064455
2025 Structural basis of Fanconi anemia pathway activation by FANCM. The EMBO journal 6 40447800
2016 Biochemical Activities and Genetic Functions of the Drosophila melanogaster Fancm Helicase in DNA Repair. Genetics 6 27466228
2010 Stabilizing and remodeling the blocked DNA replication fork: anchoring FANCM and the Fanconi anemia damage response. Molecular cell 6 20347418
2024 Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression. Cellular and molecular life sciences : CMLS 5 38847937

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