Affinage

FAN1

Fanconi-associated nuclease 1 · UniProt Q9Y2M0

Length
1017 aa
Mass
114.2 kDa
Annotated
2026-04-28
59 papers in source corpus 32 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAN1 is a structure-specific nuclease that maintains genome integrity at interstrand crosslinks, stalled replication forks, and trinucleotide repeat sequences. Its VRR_nuc domain confers 5' flap endonuclease and 5'→3' exonuclease activities, cleaving DNA at ~3-nucleotide intervals; at ICL sites it is recruited via its UBZ domain binding monoubiquitinated FANCD2, while at stalled forks it acts through a FANCD2-dependent but UBZ-independent mechanism involving the BLM–FANCD2 complex (PMID:20603073, PMID:25135477, PMID:25430771). FAN1 prevents somatic CAG/CTG trinucleotide repeat expansion by two converging mechanisms: its nuclease activity, activated by RFC–PCNA loading on extrahelical repeat extrusions, excises the looped strand to promote contraction by Polδ, and its N-terminal SPYF motif sequesters MLH1 to restrict pro-expansion MutSβ/MutLγ MMR complex assembly—activities whose loss accelerates Huntington disease and Fragile X repeat expansion in mouse and iPSC models (PMID:34469738, PMID:37549289, PMID:41145416, PMID:34718701). FAN1 protein levels are cell-cycle regulated through APC/C^Cdh1-mediated proteasomal degradation and stabilized by USP7 deubiquitination, while CDK-dependent phosphorylation at S126 modulates its MLH1 interaction (PMID:22854063, PMID:34330701, PMID:41786746). Loss-of-function mutations in FAN1 cause karyomegalic interstitial nephritis, linked to failed ICL repair and resultant polyploidy in renal tubular cells (PMID:26980188).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2010 High

    Four simultaneous studies established FAN1 as a novel structure-specific nuclease with 5' flap endonuclease and 5'→3' exonuclease activities recruited to ICL damage sites via its UBZ domain binding monoubiquitinated FANCD2, resolving how cells engage a dedicated nuclease for crosslink processing.

    Evidence Independent shRNA/siRNA screens, in vitro nuclease assays, Co-IP of UBZ–ubFANCD2 interaction, immunofluorescence foci, domain mutagenesis in human cells and DT40 knockouts

    PMID:20603015 PMID:20603016 PMID:20603073 PMID:20671156 PMID:21115814

    Open questions at the time
    • Structural basis of how FAN1 engages ICL substrates was unknown
    • Whether FAN1 acted solely within or also outside the canonical FA pathway was unresolved
    • The mechanistic basis for 5' flap specificity was not explained
  2. 2014 High

    Crystal structures of human and Pseudomonas FAN1 revealed the molecular basis for its ~3-nt iterative cleavage mechanism, head-to-tail dimerization on flap DNA, and a 5'-phosphate anchor requirement, explaining how FAN1 excises ICL lesions through flanking incisions.

    Evidence X-ray crystallography of human FAN1–DNA and PaFAN1–DNA complexes, active-site mutagenesis, in vitro nuclease assays

    PMID:24981866 PMID:25319828 PMID:25430771 PMID:25500724

    Open questions at the time
    • How FAN1 operates on chromatin substrates in vivo was not addressed
    • The role of FAN1 dimerization in cellular ICL repair was not tested
    • No structural data on FAN1 with an actual crosslinked substrate existed
  3. 2014 High

    FAN1 was shown to act at stalled replication forks through a FANCD2-dependent but UBZ-independent mechanism involving the BLM–FANCD2 complex, separating its fork-protective role from its ICL recruitment mechanism.

    Evidence Co-IP, chromatin fractionation, DNA fiber analysis, nuclease-dead mutant in human cells with siRNA knockdown of FANCD2, BLM, MRE11

    PMID:25135477

    Open questions at the time
    • The molecular basis of UBZ-independent FANCD2 recruitment at forks was unknown
    • How MRE11 gates FAN1 access to nascent DNA in the absence of FANCD2 was not structurally resolved
  4. 2016 High

    Mouse knockin and knockout models demonstrated that FAN1 nuclease activity restrains replication fork progression and prevents cancer, and that its UBZ–ubFANCD2 interaction is dispensable for ICL repair per se but critical for fork stability, fundamentally reframing FAN1's primary physiological role.

    Evidence Fan1 nuclease-defective knockin mice, cancer incidence monitoring, UBZ mutant knockin, DNA fiber analysis, epistasis with FA genes and SNM1A

    PMID:26797144 PMID:26980189

    Open questions at the time
    • The non-ICL substrates processed by FAN1 at stalled forks were not identified
    • Whether FAN1's fork-protective function extends to repeat sequences was unexplored
  5. 2016 High

    FAN1 nuclease-defective mice developed karyomegalic interstitial nephritis with polyploid renal nuclei, establishing the disease mechanism as a failure of ICL repair leading to endoreduplication.

    Evidence Fan1 nuclease-dead knockin mouse histology, flow cytometry for ploidy, ICL-induced polyploidy in fibroblasts

    PMID:26980188

    Open questions at the time
    • The identity of the endogenous ICL-inducing agent in kidney was not established
    • Whether other tissues show subclinical polyploidy was not fully assessed
  6. 2019 High

    FAN1 was identified as a suppressor of somatic CAG repeat expansion in Huntington disease models, with overexpression reducing and knockdown increasing expansion, revealing an unexpected genome stability role at trinucleotide repeats.

    Evidence FAN1 overexpression/knockdown in HD patient-derived iPSCs and neurons, repeat-length PCR, nuclease-dead mutant analysis, direct DNA binding assay

    PMID:30358836

    Open questions at the time
    • The mechanism by which FAN1 prevented expansion (binding vs. cleavage) was debated—nuclease-independent stabilization was reported
    • Whether FAN1 acted directly on repeat extrusions or indirectly through MMR was unknown
  7. 2020 High

    Mouse genetic epistasis showed that MLH1 is required for the repeat-destabilizing effect of FAN1 loss, and FAN1 was shown to interact with MLH1 and MSH2 on chromatin after alkylation damage, linking FAN1 to mismatch repair machinery.

    Evidence Fan1/Mlh1 double-knockout mice with Htt CAG knock-in, Co-IP of FAN1–MLH1/MSH2 after O6-meG damage, immunofluorescence

    PMID:31955481 PMID:32876667

    Open questions at the time
    • The molecular interface between FAN1 and MLH1 was not mapped
    • Whether FAN1–MLH1 interaction directly inhibited MMR or redirected it was unclear
  8. 2021 High

    Mapping of the FAN1 SPYF motif for MLH1 binding, CDK-dependent S126 phosphorylation modulating this interaction, and detailed biochemistry of FAN1 cleavage patterns on slipped CAG/CTG DNA established dual mechanisms—sequestration of MLH1 from pro-expansion MMR plus direct nucleolytic removal of slip-outs.

    Evidence SPYF motif and S126 mutagenesis, Co-IP, ICL and CAG/CTG slip-out repair assays, CDK inhibitor treatment, in vitro cleavage pattern mapping on slipped DNA

    PMID:34330701 PMID:34469738 PMID:34718701 PMID:34879276

    Open questions at the time
    • How S126 phosphorylation is coordinated with replication timing at repeat loci was not resolved
    • Whether FAN1 dimerization on slip-outs has the same architecture as on ICL substrates was unknown
    • In vivo contribution of SPYF-MLH1 versus nuclease activity to repeat protection was not quantitatively separated
  9. 2022 High

    Rare FAN1 coding variants in the nuclease and DNA-binding domains were shown to correlate with reduced nuclease activity in vitro and earlier Huntington disease onset, with CRISPR knockin of nuclease-dead FAN1 phenocopying complete FAN1 loss for CAG expansion, establishing nuclease activity as the critical protective function.

    Evidence Exome sequencing, purified FAN1 variant biochemistry, CRISPR knockin of nuclease-inactive FAN1 in iPSCs, CAG expansion quantification

    PMID:35379994

    Open questions at the time
    • Whether partial nuclease activity from hypomorphic alleles yields proportional clinical benefit was not established in vivo
    • Structural basis for how specific variants impair nuclease function was not determined
  10. 2023 High

    Reconstitution showed RFC–PCNA activate FAN1 nuclease on extrahelical CAG extrusions at physiological ionic strength, conferring strand directionality and enabling a short-patch excision-repair mechanism that competes with MutSβ-dependent MMR, explaining how FAN1 and MMR compete for the same substrate.

    Evidence In vitro reconstitution with purified FAN1, RFC, PCNA on extrahelical extrusion substrates; cell extract assay

    PMID:37549289

    Open questions at the time
    • Structural basis of PCNA–FAN1 interaction was not resolved
    • Whether RFC–PCNA similarly regulate FAN1 at ICL substrates was not tested
  11. 2025 High

    Cryo-EM structures of the PCNA–FAN1–DNA ternary complex revealed R507 as the direct PCNA contact; reconstitution with Polδ showed FAN1 incision followed by polymerase fill-in causes repeat contraction; FAN1 was additionally shown to directly inhibit MutLγ activation by MutSβ, establishing a complete pathway from lesion recognition to contraction.

    Evidence Cryo-EM structure determination, R507H mutant biochemistry, full reconstitution with FAN1/RFC/PCNA/MutSβ/MutLγ/Polδ

    PMID:40368883 PMID:40368897 PMID:41145416

    Open questions at the time
    • In vivo validation of the R507-PCNA interface for repeat protection is lacking
    • Whether FAN1 inhibition of MutLγ occurs through direct protein–protein contact or substrate competition was not fully distinguished
    • No in vivo structure of FAN1 operating at an endogenous repeat locus exists
  12. 2026 High

    USP7 was identified as a deubiquitinase that stabilizes FAN1 protein levels by counteracting proteasomal degradation, with USP7 depletion reducing FAN1 chromatin association and accelerating both ICL sensitivity and CAG repeat expansion.

    Evidence Co-IP of USP7–FAN1, western blot protein stability, chromatin fractionation, ICL and CAG expansion assays in RPE-1 cells

    PMID:41786746

    Open questions at the time
    • The specific ubiquitin sites on FAN1 targeted by USP7 were not mapped
    • How APC/C^Cdh1-mediated degradation and USP7 stabilization are coordinated across the cell cycle is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of endogenous ICL-generating agents in kidney tissue, the in vivo structural dynamics of FAN1 at endogenous repeat loci, the quantitative partitioning of FAN1's protective effect between nuclease activity and MLH1 sequestration, and the therapeutic potential of modulating FAN1 protein levels or activity to delay trinucleotide repeat expansion diseases.
  • No endogenous crosslinking agent in kidney has been identified
  • Relative contribution of SPYF-MLH1 sequestration versus nuclease activity to repeat protection has not been quantitatively determined in vivo
  • No pharmacological activator of FAN1 has been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 10 GO:0016787 hydrolase activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-73894 DNA Repair 9 R-HSA-69306 DNA Replication 2 R-HSA-1640170 Cell Cycle 1
Partners
BLMFANCD2MLH1MSH2PCNARFCUSP7
Complex memberships
BLM-FANCD2-FAN1PCNA-RFC-FAN1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 FAN1 (KIAA1018) possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched DNA structures, and is recruited to sites of interstrand crosslink (ICL) damage through its ubiquitin-binding zinc finger (UBZ) domain binding to monoubiquitinated FANCD2. shRNA screen, in vitro nuclease assay, co-immunoprecipitation, immunofluorescence colocalization at DNA damage foci, UBZ domain mutant analysis Molecular cell High 20603073
2010 FAN1 interacts with and is recruited to DNA damage sites by the monoubiquitinated form of FANCD2; FAN1 exhibits 5' flap endonuclease activity and 5' exonuclease activity mediated by its conserved VRR_nuc domain. Co-immunoprecipitation, in vitro nuclease assay, siRNA knockdown with ICL sensitivity and genome instability readouts Cell High 20603015
2010 FAN1 (KIAA1018) is a 5'→3' exonuclease and structure-specific endonuclease preferentially incising 5' flaps; its UBZ domain interacts with monoubiquitylated FANCD2 for recruitment to ICL damage sites; depletion causes ICL hypersensitivity and chromosomal instability. In vitro nuclease assay, co-immunoprecipitation, siRNA knockdown, chromosomal instability assay Cell High 20603016
2010 FAN1 promotes ICL repair in a manner strictly dependent on its ability to accumulate at sites of DNA damage, and this accumulation relies on monoubiquitylation of the FANCI-FANCD2 (ID) complex. siRNA knockdown, fluorescence microscopy, epistasis analysis with ID complex mutants Science High 20671156
2010 FAN1 localizes to stalled replication forks (colocalizing with RPA) in a UBZ domain-dependent manner, and is a nuclear protein forming DNA-damage-induced foci. Immunofluorescence colocalization with RPA, UBZ domain mutant analysis, siRNA knockdown Cell cycle Medium 20935496
2010 FAN1 null DT40 cells are sensitive to cisplatin and MMC but not ionizing/UV radiation, MMS, or camptothecin; double knockouts of FAN1 with FANCC or FANCJ show increased cisplatin sensitivity, indicating FAN1 participates in ICL repair both within and independently of the classical FA pathway. Gene targeting in chicken DT40 cells, drug sensitivity assays, double-mutant epistasis analysis, sister chromatid exchange assay PNAS High 21115814
2014 Crystal structures of human FAN1 reveal it cleaves DNA successively at every third nucleotide via exonuclease activity, requiring a 5'-terminal phosphate anchor at a nick or 1-2 nucleotide flap, augmented by a 3' flap; this mechanism allows FAN1 to excise an ICL from one strand through flanking incisions. X-ray crystallography (FAN1-DNA co-crystal structures), in vitro biochemical assay, active-site mutagenesis Science High 25430771
2014 Human FAN1 forms a head-to-tail dimer in complex with 5' flap DNA; two FAN1 molecules cooperate to locate the lesion, orient the DNA, and unwind a 5' flap for subsequent incision; structure-informed mutations disrupting dimerization, substrate orientation, or flap unwinding impair nuclease activity. X-ray crystallography (three crystal structures), biochemical nuclease assay, structure-guided mutagenesis Nature communications High 25500724
2014 FAN1 VRR_nuc domain is monomeric (unlike bacterial/viral homologs which dimerize) due to an insertion that packs against the dimerization interface, and cleaves 5' flap structures but not Holliday junctions. X-ray crystallography of three VRR_nuc representatives, in vitro nuclease assay, structural modeling Cell reports High 24981866
2014 FAN1 is recruited to aphidicolin-stalled replication forks via a FANCD2-dependent (but FA core complex- and UBZ domain-independent) mechanism; FAN1 joins the BLM-FANCD2 complex and uses its nuclease activity for fork restart; in the absence of FANCD2, MRE11-promoted FAN1 access leads to nucleolytic degradation of nascent DNA. Co-immunoprecipitation, chromatin fractionation, siRNA knockdown, DNA fiber analysis (replication fork assay), nuclease-defective mutant analysis Molecular and cellular biology High 25135477
2014 Crystal structure of Pseudomonas aeruginosa FAN1 in complex with 5' flap DNA shows all four domains participate in DNA recognition with each playing a specific role; a six-helix bundle connecting to the VRR_nuc domain enables incision several bases from the junction; a clamping motion facilitates nucleolytic cleavage. X-ray crystallography, biochemical nuclease assay Genes & development High 25319828
2015 FAN1 efficiently promotes endonucleolytic incision of 5' flap DNA complexed with RPA at the proper site, demonstrating that RPA-coated single-stranded DNA does not block FAN1 activity at stalled replication forks. In vitro nuclease assay with purified recombinant human FAN1 and RPA on 5'-flapped DNA substrates Journal of biochemistry Medium 25922199
2016 Fan1 recruitment to ICLs by ubiquitinated Fancd2 is dispensable for ICL repair per se; instead, Fan1 recruitment and nuclease activity restrain replication fork progression and prevent chromosome abnormalities when forks stall; Fan1 nuclease-defective knockin mice are cancer-prone; a cancer-associated Fan1 variant abolishing Ub-Fancd2 recruitment causes genetic instability without affecting ICL repair. Fan1 knockin mouse (nuclease-defective), cancer incidence monitoring, DNA fiber analysis, epistasis with FANCD2 ubiquitination, chromosome aberration assay Science High 26797144
2016 In Fan1-deficient mice, the UBZ domain (required for FANCD2 interaction) is not required for initial rapid recruitment of FAN1 to ICLs or for ICL resistance; epistasis analyses show FAN1 has ICL repair activities independent of Fanconi anemia proteins, with activity redundant with the 5'-3' exonuclease SNM1A. Fan1-deficient mouse, UBZ domain mutant knockin, drug sensitivity assays, epistasis with FA pathway mutants and SNM1A Genes & development High 26980189
2016 Fan1 nuclease-defective knockin (Fan1nd/nd) mice develop karyomegalic interstitial nephritis; karyomegalic nuclei in kidneys are polyploid; fibroblasts from Fan1nd/nd mice become polyploid upon ICL induction, indicating FAN1 nuclease activity controls ploidy through ICL repair. Knockin mouse model (nuclease-defective point mutation), histology, flow cytometry (ploidy), drug treatment assays Genes & development High 26980188
2018 Structural analysis reveals that despite lacking a basic pocket and dimerization features of human FAN1, Pseudomonas aeruginosa FAN1 cleaves substrates at ~3-nt intervals and resolves ICLs; a conserved Arg/Lys patch recognizes phosphates near the 5' terminus; in human FAN1 the Arg/Lys patch and basic pocket play complementary roles in ICL resolution. X-ray crystallography of PaFAN1-DNA complexes, site-directed mutagenesis, in vitro ICL resolution assay Journal of biological chemistry High 29514982
2019 FAN1 binds to the expanded HTT CAG repeat DNA and suppresses CAG repeat expansion in a nuclease-independent manner; FAN1 overexpression reduces CAG repeat expansion whereas FAN1 knockdown increases it in patient-derived stem cells and neurons; stabilizing effect is FAN1 concentration- and CAG length-dependent. FAN1 overexpression and siRNA knockdown in human cells and patient-derived iPSCs/neurons, repeat-length PCR assay, DNA binding assay, nuclease-dead mutant analysis Human molecular genetics High 30358836
2020 Fan1 knockout increases somatic CAG repeat expansion of Htt knock-in CAG repeats in mice; simultaneous knockout of Mlh1 blocks Fan1-KO-induced acceleration of somatic CAG expansion, establishing a genetic interaction where MLH1 is required for the CAG repeat-destabilizing effect of FAN1 loss. Fan1 knockout mice crossed with Htt CAG knock-in mice, Mlh1 knockout double mutant, somatic repeat instability quantification Human molecular genetics High 32876667
2020 FAN1 missense variants p.Arg507His and p.Arg377Trp (within or near the DNA-binding domain) reduce FAN1's DNA-binding activity and its capacity to rescue MMC-induced cytotoxicity; FAN1 knockout increases CAG repeat expansion in HD iPSCs. In vitro DNA-binding assay, MMC complementation assay, FAN1 knockout iPSC CAG repeat expansion assay American journal of human genetics High 32589923
2020 FAN1 is loaded onto chromatin through interaction with MLH1 following O6-methylguanine damage; FAN1 produces single-stranded DNA by its exonuclease activity contributing to DNA damage response and apoptosis; FAN1 interacts with both MLH1 and MSH2 after alkylation damage; FAN1 focus formation requires MLH1 but not FANCD2. Co-immunoprecipitation, immunofluorescence (FAN1 foci with MLH1, ssDNA), siRNA knockdown, sub-G1 and caspase-9 apoptosis assays Genes to cells Medium 31955481
2021 FAN1 contains a conserved SPYF motif at its N-terminus that binds MLH1; FAN1 restricts MLH1 recruitment by MSH3 to inhibit assembly of a functional MMR complex that would otherwise promote CAG repeat expansion; FAN1 also promotes accurate repair via its nuclease activity. Mutagenesis of SPYF motif, co-immunoprecipitation, CAG repeat expansion assays in patient-derived cells Cell reports High 34469738
2021 Specific amino acid residues in two adjacent FAN1 motifs are critical for MLH1 binding; disruption of the FAN1-MLH1 interaction causes ICL hypersensitivity and defective repair of CAG/CTG slip-outs; FAN1-S126 phosphorylation by cyclin-dependent kinase activity hinders FAN1-MLH1 association and is attenuated upon ICL induction. Site-directed mutagenesis, co-immunoprecipitation, ICL sensitivity assay, CAG/CTG slip-out repair assay, phosphorylation site mapping, CDK inhibitor treatment Science advances High 34330701
2021 FAN1 exonuclease (but not endonuclease) activity pauses at specific sites within CAG and CTG slip-out repeats (5'-C↓A↓GC↓A↓G-3' and 5'-C↓T↓G↓C↓T↓G-3'); FAN1 binds, dimerizes, and cleaves slipped DNAs through iterative cycles; nuclease-ligand naphthyridine-azaquinolone protecting slip-outs from FAN1 exo- but not endo-nucleolytic digestion requires FAN1 for in vivo repeat contraction. In vitro nuclease assay with purified FAN1 on slipped-DNA substrates, cleavage pattern mapping, dimerization analysis, ligand competition assay Cell reports High 34879276
2022 Rare FAN1 coding variants in the DNA-binding and nuclease domains are associated with earlier HD onset; nuclease activities of purified variants in vitro correlate with residual age at motor onset; mutating endogenous FAN1 to nuclease-inactive form in iPSCs leads to CAG expansion rates similar to complete FAN1 knockout, establishing nuclease activity as the key protective function. Exome sequencing, in vitro nuclease assay with purified FAN1 variants, CRISPR knockin of nuclease-inactive FAN1 in iPSCs, CAG repeat expansion assay Nature neuroscience High 35379994
2023 FAN1 nuclease function on CAG triplet repeat extrusions is activated by RFC, PCNA, and ATP at physiological ionic strength; RFC-PCNA confer strand directionality to FAN1; PCNA-FAN1 physical interaction is required; FAN1-dependent CAG extrusion removal in cell extracts proceeds via a short patch excision-repair mechanism competing with MutSβ-dependent MMR. In vitro nuclease assay with purified FAN1, RFC, PCNA on extrahelical extrusion substrates, cell extract assay, PCNA-FAN1 interaction assay PNAS High 37549289
2012 FAN1 protein levels are regulated during cell cycle; FAN1 is degraded during mitotic exit as a substrate of APC/CCdh1 (not APC/CCdc20) through KEN box and D-box degrons; FAN1 levels affect progression to mitotic exit. Western blotting during cell cycle, Cdh1/Cdc20 overexpression, KEN box/D-box mutant analysis, flow cytometry Chinese journal of cancer Medium 22854063
2025 Cryo-EM structures of PCNA-FAN1-DNA complex reveal that FAN1 R507 directly contacts PCNA D232; the R507H mutation attenuates FAN1-PCNA complex assembly on CAG extrahelical extrusions and abolishes PCNA-FAN1-dependent cleavage; PCNA modulates FAN1 activity upon ternary complex formation. Cryo-EM structure determination, biophysical interaction studies, in vitro nuclease assay with R507H mutant and PCNA Nature communications High 40368883 40368897
2025 FAN1 preferentially targets the looped strand of CAG extrahelical extrusions; RFC-PCNA stimulate and direct FAN1 nuclease to the 3' boundary of the loop while restricting exonuclease activity; no pre-existing nick is required; FAN1 action followed by Polδ causes repeat contraction; FAN1 also directly inhibits MutLγ, preventing its activation by MutSβ. In vitro reconstitution with purified human proteins (FAN1, RFC, PCNA, MutLγ, MutSβ, Polδ), nuclease assay, repeat expansion/contraction assay Nature communications High 41145416
2026 USP7 deubiquitinase interacts with FAN1 and stabilizes FAN1 protein levels by preventing its proteasomal degradation through deubiquitination; USP7 depletion reduces FAN1 chromatin association, increases ICL sensitivity, and accelerates CAG repeat expansion. Co-immunoprecipitation (USP7-FAN1 interaction), western blot (protein stability), chromatin fractionation, ICL sensitivity assay, CAG repeat expansion assay in RPE-1 cells Nature communications High 41786746
2024 miR-124-3p selectively targets the reference allele at rs3512 in the FAN1 3'-UTR, reducing FAN1 mRNA stability and levels; the alternative allele at rs3512 renders FAN1 mRNA less susceptible to miR-124-3p-mediated degradation, resulting in increased FAN1 expression. Antagomir treatment, 3'-UTR reporter assays with swapped alleles, allelic imbalance analysis PNAS High 38607933
2021 In a Fragile X mouse model, Fan1 nuclease domain point mutation has the same effect on CGG repeat expansion as a null mutation; FAN1 and EXO1 have additive effects protecting against MSH3-dependent expansions; loss of FANCD2 has no effect on expansions, indicating FAN1 protects against repeat expansion independently of the canonical FA pathway and requires its nuclease domain. FAN1 nuclease-domain point mutant knockin mouse, Fan1/Exo1 double knockout, Fancd2 knockout, somatic repeat instability quantification Nucleic acids research High 34718701

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Molecular cell 282 20603073
2010 Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell 249 20603015
2010 Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 220 20603016
2010 FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science (New York, N.Y.) 209 20671156
2012 FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nature genetics 184 22772369
2019 FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat. Human molecular genetics 106 30358836
2016 Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. Science (New York, N.Y.) 104 26797144
2015 Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. Gastroenterology 83 26052075
2010 KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proceedings of the National Academy of Sciences of the United States of America 77 21115814
2020 Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington's disease knock-in mice is blocked by Mlh1 knock-out. Human molecular genetics 64 32876667
2022 Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset. Nature neuroscience 63 35379994
2013 Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism. Proceedings of the National Academy of Sciences of the United States of America 63 24344280
2018 FAN1 protects against repeat expansions in a Fragile X mouse model. DNA repair 61 29990673
2014 FANCD2-controlled chromatin access of the Fanconi-associated nuclease FAN1 is crucial for the recovery of stalled replication forks. Molecular and cellular biology 60 25135477
2014 DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1. Science (New York, N.Y.) 59 25430771
2020 Genetic and Functional Analyses Point to FAN1 as the Source of Multiple Huntington Disease Modifier Effects. American journal of human genetics 57 32589923
2021 FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease. Cell reports 55 34469738
2021 FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders. Journal of Huntington's disease 49 33579867
2016 Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. Genes & development 48 26980189
2021 FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats. Science advances 35 34330701
2016 Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice. Genes & development 35 26980188
2014 Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer. Nature communications 34 25500724
2022 Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1. Kidney international 31 35931300
2012 On the role of FAN1 in Fanconi anemia. Blood 30 22611161
2023 FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America 23 37549289
2021 FAN1 exo- not endo-nuclease pausing on disease-associated slipped-DNA repeats: A mechanism of repeat instability. Cell reports 23 34879276
2013 The conserved Fanconi anemia nuclease Fan1 and the SUMO E3 ligase Pli1 act in two novel Pso2-independent pathways of DNA interstrand crosslink repair in yeast. DNA repair 23 24192486
2014 FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric virus-type replication-repair nuclease domain. Cell reports 21 24981866
2014 Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1. Genes & development 20 25319828
2010 Human KIAA1018/FAN1 localizes to stalled replication forks via its ubiquitin-binding domain. Cell cycle (Georgetown, Tex.) 20 20935496
2017 Structural and functional relationships of FAN1. DNA repair 19 28623094
2021 FAN1's protection against CGG repeat expansion requires its nuclease activity and is FANCD2-independent. Nucleic acids research 17 34718701
2018 The RecQ-like helicase HRQ1 is involved in DNA crosslink repair in Arabidopsis in a common pathway with the Fanconi anemia-associated nuclease FAN1 and the postreplicative repair ATPase RAD5A. The New phytologist 17 29577315
2015 The nuclease FAN1 is involved in DNA crosslink repair in Arabidopsis thaliana independently of the nuclease MUS81. Nucleic acids research 15 25779053
2011 FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer. Breast cancer research and treatment 13 21858661
2010 DNA repair has a new FAN1 club. Molecular cell 11 20670886
2024 Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease. Proceedings of the National Academy of Sciences of the United States of America 9 38607933
2020 Karyomegalic interstitial nephritis with a novel FAN1 gene mutation and concurrent ALECT2 amyloidosis. BMC nephrology 9 32111193
2020 MLH1-mediated recruitment of FAN1 to chromatin for the induction of apoptosis triggered by O6 -methylguanine. Genes to cells : devoted to molecular & cellular mechanisms 8 31955481
2015 Human FAN1 promotes strand incision in 5'-flapped DNA complexed with RPA. Journal of biochemistry 8 25922199
2021 New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene. BMC medical genomics 7 34126972
2012 Human KIAA1018/FAN1 nuclease is a new mitotic substrate of APC/C(Cdh1). Chinese journal of cancer 7 22854063
2023 Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys. Antioxidants (Basel, Switzerland) 6 37107275
2023 Modeling of FAN1-Deficient Kidney Disease Using a Human Induced Pluripotent Stem Cell-Derived Kidney Organoid System. Cells 6 37759541
2020 Common variants in FAN1, located in 15q13.3, confer risk for schizophrenia and bipolar disorder in Han Chinese. Progress in neuro-psychopharmacology & biological psychiatry 6 32450113
2018 Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease. The Journal of biological chemistry 6 29514982
2020 Novel Homozygous FAN1 Mutation in a Familial Case of Karyomegalic Interstitial Nephritis. Indian journal of nephrology 5 33273795
2025 A FAN1 point mutation associated with accelerated Huntington's disease progression alters its PCNA-mediated assembly on DNA. Nature communications 4 40368883
2025 Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair. Nature communications 4 40368897
2024 Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family. International journal of molecular sciences 4 38892095
2025 FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations. Nature communications 3 40082407
2025 Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1. Nature communications 2 41145416
2024 Karyomegalic interstitial nephritis, a fascinating histopathologic entity for pathologists: Be watchful of the FAN1 gene mutations. Indian journal of pathology & microbiology 2 38847221
2024 Structural and molecular basis of FAN1 defects in promoting Huntington's disease. bioRxiv : the preprint server for biology 2 39416186
2024 A case of karyomegalic interstitial nephritis without FAN1 mutations in the setting of brentuximab, ifosfamide, and carboplatin exposure. BMC nephrology 2 39543462
2021 SPYing on triplet repeat expansions: Insights into FAN1-MLH1 interaction and regulation. Cell reports 2 34525375
2024 FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Genes 1 39596669
2026 USP7 deubiquitinase stabilizes FAN1 to support DNA crosslink repair and suppress CAG repeat expansion. Nature communications 0 41786746
2024 A rare multisystemic disorder with chronic kidney disease: Karyomegalic interstitial nephritis due to homozygous FAN1 c.2260C>T variant. Nephrology (Carlton, Vic.) 0 39294548