Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.
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FAN1 exhibits 5'-flap endonuclease and 5'-3' exonuclease activities mediated by the VRR_nuc domain
"FAN1 exhibits endonuclease activity toward 5' flaps and has 5' exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain"
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FAN1 is recruited to DNA damage sites by monoubiquitinated FANCD2
"a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2"
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C. elegans fan-1 deletion causes ICL sensitivity
"Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability"
Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.
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FAN1/KIAA1018 is a 5'-3' exonuclease and structure-specific endonuclease recruited to DNA damage via UBZ domain interaction with monoubiquitinated FANCD2
"KIAA1018 is a 5'-->3' exonuclease and a structure-specific endonuclease that preferentially incises 5' flaps...recruitment to DNA damage through interaction of its UBZ domain with monoubiquitylated FANCD2"
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C. elegans fan-1 mutants show sensitivity to ICL-inducing agents and chromosomal instability
"human cells depleted of KIAA1018 are sensitized to ICL-inducing agents and display chromosomal instability"
A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.
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FAN1 has 5'-3' exonuclease activity and endonuclease activity on nicked and branched structures
"FAN1 possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched structures"
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FAN1 is recruited to DNA damage through ubiquitinated FANCD2/FANCI complex via its UBZ domain
"FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2"
Systematic analysis of DNA crosslink repair pathways during development and aging in Caenorhabditis elegans.
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FAN-1 contributes to ICL resolution in C. elegans in a replication-dependent manner
"The analysis also revealed contributions of homologous recombination (BRC-1/BRCA1), the MUS-81, EXO-1, SLX-1 and FAN-1 nucleases, and the DOG-1 (FANCJ) helicase in ICL resolution, influenced by the replicative-status of the cell/tissue"
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FCD-2 (FANCD2) is not critical for ICL repair in C. elegans, suggesting FAN-1 can act partly independently
"No obvious or critical role in ICL repair was seen for...the Fanconi-related proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2)"
FAN1-mediated translesion synthesis and POLQ/HELQ-mediated end joining generate interstrand crosslink-induced mutations.
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In C. elegans, FAN-1 is required for SNV formation during ICL repair via translesion synthesis
"we found these SNVs to depend on the functionality of the Fanconi anemia-associated nuclease FAN1"
LINC complexes promote homologous recombination in part through inhibition of nonhomologous end joining.
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The SUN-domain protein UNC-84 recruits the FA nuclease FAN-1 to the nucleoplasm in C. elegans, coupling
nuclear-envelope (LINC) biology to interstrand crosslink processing; UNC-84/LINC suppresses NHEJ in favor of HR.
"nuclease FAN-1 to the nucleoplasm, suggesting that UNC-84 both alters the extent
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The LINC complex functions with the Fanconi anemia pathway to suppress NHEJ in favor of homologous recombination,
safeguarding the germline genome during crosslink repair.
"LINC) functions with the Fanconi anemia (FA) pathway to suppress NHEJ in favor of HR
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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.
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C. elegans FANCM/FNCM-1 relocalizes upon replication stress (hydroxyurea) and colocalizes with FANCD2/FCD-2,
establishing a germline FA-pathway relocalization program that, per falcon deep research, also recruits the
downstream nuclease FAN-1 (FAN-1-specific recruitment is reported in the paper body, not the abstract).
"FANCM/CeFNCM-1 relocalizes upon hydroxyurea exposure and colocalizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5, suggesting coordination
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FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism.
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FAN1 has a strand-directed nuclease activity, activated by RFC, PCNA, and ATP at physiological ionic strength,
that removes triplet-repeat extrahelical extrusions, extending FAN1 function beyond classical ICL unhooking.
The replisome machinery (PCNA clamp, RFC loader) is conserved, suggesting analogous regulation of worm FAN-1.
"we describe a strand-directed, extrusion-provoked nuclease function of FAN1 that
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In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, a non-ICL activity of the same nuclease.
"FAN1 prevents somatic expansion of CAG triplet repeats
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Falcon deep research report on C. elegans fan-1 (P90740)
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Falcon synthesis: worm fan-1/P90740 (ORF C01G5.8) encodes a conserved structure-specific DNA nuclease acting
mainly during interstrand crosslink repair and replication-associated DNA damage processing, recruited in the
germline by FNCM-1/FCD-2 and relocalized to the nucleoplasm by UNC-84 after crosslinks, and controlling repair
pathway choice (promoting TLS, limiting TMEJ).
"The best-supported annotation is that **fan-1/P90740** encodes a **structure-specific DNA nuclease** acting mainly during **interstrand crosslink repair** and **replication-associated DNA damage processing**, likely via incision/unhooking of branched/5′-flap-like intermediates; it acts in FA-linked but partly parallel pathways, is recruited in the germline by **FNCM-1/FCD-2**, and is relocalized to the nucleoplasm by **UNC-84** after crosslinks.
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Falcon deep research synthesis: in a defined psoralen-ICL assay, fan-1 acts in a pathway parallel to canonical
Fanconi anemia factors, with its processing generating substrates for translesion synthesis (TLS) polymerases;
fan-1 mutants resemble polh-1/rev-1/rev-3 TLS mutants and FAN-1 additionally suppresses deletion-prone POLQ/HELQ end joining (TMEJ).
"Recent worm work on defined psoralen ICL repair outcomes argues that FAN1 can act **in a pathway parallel to canonical Fanconi anemia factors**, and that its processing may generate substrates for **translesion synthesis (TLS)** polymerases.
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A map of the interactome network of the metazoan C. elegans.
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High-throughput Y2H screen detected FAN-1 protein-protein interactions
"more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens"
Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.
Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on Enzyme Commission mapping
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping