ID FEN1_HUMAN Reviewed; 380 AA. AC P39748; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 27-MAR-2024, entry version 221. DE RecName: Full=Flap endonuclease 1 {ECO:0000255|HAMAP-Rule:MF_03140}; DE Short=FEN-1 {ECO:0000255|HAMAP-Rule:MF_03140}; DE EC=3.1.-.- {ECO:0000255|HAMAP-Rule:MF_03140}; DE AltName: Full=DNase IV; DE AltName: Full=Flap structure-specific endonuclease 1 {ECO:0000255|HAMAP-Rule:MF_03140}; DE AltName: Full=Maturation factor 1; DE Short=MF1; DE Short=hFEN-1; GN Name=FEN1 {ECO:0000255|HAMAP-Rule:MF_03140}; Synonyms=RAD2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=8007985; DOI=10.1128/mcb.14.7.4878-4888.1994; RA Murray J.M., Tavassoli M., Al-Harithy R., Sheldrick K.S., Lehmann A.R., RA Carr A.M., Watts F.Z.; RT "Structural and functional conservation of the human homolog of the RT Schizosaccharomyces pombe rad2 gene, which is required for chromosome RT segregation and recovery from DNA damage."; RL Mol. Cell. Biol. 14:4878-4888(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Leukemic T-cell; RX PubMed=7774922; DOI=10.1016/0888-7543(95)80129-a; RA Hiraoka L.R., Harrington J.J., Gerhard D.S., Lieber M.R., Hsieh C.-L.; RT "Sequence of human FEN-1, a structure-specific endonuclease, and RT chromosomal localization of the gene (FEN1) in mouse and human."; RL Genomics 25:220-225(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PARTIAL PROTEIN SEQUENCE, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=7961795; DOI=10.1016/s0021-9258(19)61935-6; RA Robins P., Pappin D.J.C., Wood R.D., Lindahl T.; RT "Structural and functional homology between mammalian DNase IV and the 5'- RT nuclease domain of Escherichia coli DNA polymerase I."; RL J. Biol. Chem. 269:28535-28538(1994). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE-BINDING SITES, AND MUTAGENESIS OF RP ASP-34; ASP-86; ARG-103; GLU-158; ASP-179; ASP-181; GLY-231 AND ASP-233. RX PubMed=8621570; DOI=10.1074/jbc.271.16.9173; RA Shen B., Nolan J.P., Sklar L.A., Park M.S.; RT "Essential amino acids for substrate binding and catalysis of human flap RT endonuclease 1."; RL J. Biol. Chem. 271:9173-9176(1996). RN [8] RP INTERACTION WITH PCNA. RX PubMed=9305916; DOI=10.1074/jbc.272.39.24522; RA Gary R., Ludwig D.L., Cornelius H.L., MacInnes M.A., Park M.S.; RT "The DNA repair endonuclease XPG binds to proliferating cell nuclear RT antigen (PCNA) and shares sequence elements with the PCNA-binding regions RT of FEN-1 and cyclin-dependent kinase inhibitor p21."; RL J. Biol. Chem. 272:24522-24529(1997). RN [9] RP FUNCTION. RX PubMed=10744741; DOI=10.1074/jbc.275.14.10498; RA Tom S., Henricksen L.A., Bambara R.A.; RT "Mechanism whereby proliferating cell nuclear antigen stimulates flap RT endonuclease 1."; RL J. Biol. Chem. 275:10498-10505(2000). RN [10] RP INTERACTION WITH PCNA AND P300, AND ACETYLATION AT LYS-354; LYS-375; RP LYS-377 AND LYS-380. RX PubMed=11430825; DOI=10.1016/s1097-2765(01)00272-6; RA Hasan S., Stucki M., Hassa P.O., Imhof R., Gehrig P., Hunziker P., RA Hubscher U., Hottiger M.O.; RT "Regulation of human flap endonuclease-1 activity by acetylation through RT the transcriptional coactivator p300."; RL Mol. Cell 7:1221-1231(2001). RN [11] RP FUNCTION, SUBSTRATE-BINDING SITES ARG-47 AND ARG-70, AND MUTAGENESIS OF RP ARG-29; ARG-47; ARG-70; ARG-73 AND LYS-80. RX PubMed=11986308; DOI=10.1074/jbc.m111941200; RA Qiu J., Bimston D.N., Partikian A., Shen B.; RT "Arginine residues 47 and 70 of human flap endonuclease-1 are involved in RT DNA substrate interactions and cleavage site determination."; RL J. Biol. Chem. 277:24659-24666(2002). RN [12] RP INTERACTION WITH DDX11. RX PubMed=18499658; DOI=10.1074/jbc.m802696200; RA Farina A., Shin J.H., Kim D.H., Bermudez V.P., Kelman Z., Seo Y.S., RA Hurwitz J.; RT "Studies with the human cohesin establishment factor, ChlR1. Association of RT ChlR1 with Ctf18-RFC and Fen1."; RL J. Biol. Chem. 283:20925-20936(2008). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND MUTAGENESIS OF RP SER-187. RX PubMed=18443037; DOI=10.1128/mcb.00200-08; RA Guo Z., Qian L., Liu R., Dai H., Zhou M., Zheng L., Shen B.; RT "Nucleolar localization and dynamic roles of flap endonuclease 1 in RT ribosomal DNA replication and damage repair."; RL Mol. Cell. Biol. 28:4310-4319(2008). RN [14] RP INTERACTION WITH POLB. RX PubMed=19336415; DOI=10.1093/nar/gkp201; RA Guo Z., Zheng L., Dai H., Zhou M., Xu H., Shen B.; RT "Human DNA polymerase beta polymorphism, Arg137Gln, impairs its polymerase RT activity and interaction with PCNA and the cellular base excision repair RT capacity."; RL Nucleic Acids Res. 37:3431-3441(2009). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-80 AND LYS-375, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [16] RP FUNCTION, MUTAGENESIS OF ARG-192, METHYLATION AT ARG-19; ARG-100; ARG-104 RP AND ARG-192, AND PHOSPHORYLATION AT SER-187. RX PubMed=20729856; DOI=10.1038/nchembio.422; RA Guo Z., Zheng L., Xu H., Dai H., Zhou M., Pascua M.R., Chen Q.M., Shen B.; RT "Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA RT binding."; RL Nat. Chem. Biol. 6:766-773(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197 AND THR-364, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-255; SER-293; SER-335 AND RP THR-336, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [21] RP ALTERNATIVE INITIATION (ISOFORM FENMIT), AND SUBCELLULAR LOCATION (ISOFORM RP FENMIT). RX PubMed=23675412; DOI=10.1371/journal.pone.0062340; RA Kazak L., Reyes A., He J., Wood S.R., Brea-Calvo G., Holen T.T., Holt I.J.; RT "A cryptic targeting signal creates a mitochondrial FEN1 isoform with RT tailed R-loop binding properties."; RL PLoS ONE 8:E62340-E62340(2013). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP INTERACTION WITH POLB. RX PubMed=26760506; DOI=10.18632/oncotarget.6849; RA Zhou T., Pan F., Cao Y., Han Y., Zhao J., Sun H., Zhou X., Wu X., He L., RA Hu Z., Chen H., Shen B., Guo Z.; RT "R152C DNA Pol beta mutation impairs base excision repair and induces RT cellular transformation."; RL Oncotarget 7:6902-6915(2016). RN [24] RP FUNCTION, AND INTERACTION WITH WDR4. RX PubMed=26751069; DOI=10.1371/journal.pbio.1002349; RA Cheng I.C., Chen B.C., Shuai H.H., Chien F.C., Chen P., Hsieh T.S.; RT "Wuho is a new member in maintaining genome stability through its RT interaction with flap endonuclease 1."; RL PLoS Biol. 14:E1002349-E1002349(2016). RN [25] RP X-RAY CRYSTALLOGRAPHY (1.88 ANGSTROMS) OF 331-350. RX PubMed=15576034; DOI=10.1016/j.str.2004.09.018; RA Bruning J.B., Shamoo Y.; RT "Structural and thermodynamic analysis of human PCNA with peptides derived RT from DNA polymerase-delta p66 subunit and flap endonuclease-1."; RL Structure 12:2209-2219(2004). RN [26] RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) OF 2-380 IN COMPLEX WITH PCNA AND RP MAGNESIUM IONS. RX PubMed=15616578; DOI=10.1038/sj.emboj.7600519; RA Sakurai S., Kitano K., Yamaguchi H., Hamada K., Okada K., Fukuda K., RA Uchida M., Ohtsuka E., Morioka H., Hakoshima T.; RT "Structural basis for recruitment of human flap endonuclease 1 to PCNA."; RL EMBO J. 24:683-693(2005). CC -!- FUNCTION: Structure-specific nuclease with 5'-flap endonuclease and 5'- CC 3' exonuclease activities involved in DNA replication and repair. CC During DNA replication, cleaves the 5'-overhanging flap structure that CC is generated by displacement synthesis when DNA polymerase encounters CC the 5'-end of a downstream Okazaki fragment. It enters the flap from CC the 5'-end and then tracks to cleave the flap base, leaving a nick for CC ligation. Also involved in the long patch base excision repair (LP-BER) CC pathway, by cleaving within the apurinic/apyrimidinic (AP) site- CC terminated flap. Acts as a genome stabilization factor that prevents CC flaps from equilibrating into structures that lead to duplications and CC deletions. Also possesses 5'-3' exonuclease activity on nicked or CC gapped double-stranded DNA, and exhibits RNase H activity. Also CC involved in replication and repair of rDNA and in repairing CC mitochondrial DNA. {ECO:0000255|HAMAP-Rule:MF_03140, CC ECO:0000269|PubMed:10744741, ECO:0000269|PubMed:11986308, CC ECO:0000269|PubMed:18443037, ECO:0000269|PubMed:20729856, CC ECO:0000269|PubMed:26751069, ECO:0000269|PubMed:7961795, CC ECO:0000269|PubMed:8621570}. CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Note=Binds 2 magnesium ions per subunit. They probably participate in CC the reaction catalyzed by the enzyme. May bind an additional third CC magnesium ion after substrate binding.; CC -!- SUBUNIT: Interacts with PCNA (PubMed:9305916, PubMed:11430825, CC PubMed:26760506, PubMed:15616578). Three molecules of FEN1 bind to one CC PCNA trimer with each molecule binding to one PCNA monomer CC (PubMed:15616578). PCNA stimulates the nuclease activity without CC altering cleavage specificity (PubMed:15616578). The C-terminal domain CC binds EP300; can bind simultaneously to both PCNA and EP300 CC (PubMed:11430825). Interacts with DDX11; this interaction is direct and CC increases flap endonuclease activity of FEN1 (PubMed:18499658). CC Interacts with WDR4; regulating its endonuclease activity CC (PubMed:26751069). Interacts with POLB (PubMed:19336415, CC PubMed:26760506). {ECO:0000255|HAMAP-Rule:MF_03140, CC ECO:0000269|PubMed:11430825, ECO:0000269|PubMed:15616578, CC ECO:0000269|PubMed:18499658, ECO:0000269|PubMed:19336415, CC ECO:0000269|PubMed:26751069, ECO:0000269|PubMed:26760506, CC ECO:0000269|PubMed:9305916}. CC -!- INTERACTION: CC P39748; P54132: BLM; NbExp=4; IntAct=EBI-707816, EBI-621372; CC P39748; Q96NY9: MUS81; NbExp=5; IntAct=EBI-707816, EBI-2370806; CC P39748; P12004: PCNA; NbExp=19; IntAct=EBI-707816, EBI-358311; CC P39748; P57081: WDR4; NbExp=8; IntAct=EBI-707816, EBI-750427; CC P39748; Q14191: WRN; NbExp=9; IntAct=EBI-707816, EBI-368417; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Nucleus, nucleolus. Nucleus, CC nucleoplasm. Note=Resides mostly in the nucleoli and relocalizes to the CC nucleoplasm upon DNA damage. CC -!- SUBCELLULAR LOCATION: [Isoform FENMIT]: Mitochondrion CC {ECO:0000255|HAMAP-Rule:MF_03140, ECO:0000269|PubMed:23675412}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=2; CC Name=1; CC IsoId=P39748-1; Sequence=Displayed; CC Name=FENMIT; CC IsoId=P39748-2; Sequence=VSP_047520; CC -!- PTM: Acetylated by EP300. Acetylation inhibits both endonuclease and CC exonuclease activity. Acetylation also reduces DNA-binding activity but CC does not affect interaction with PCNA or EP300. {ECO:0000255|HAMAP- CC Rule:MF_03140, ECO:0000269|PubMed:11430825}. CC -!- PTM: Phosphorylation upon DNA damage induces relocalization to the CC nuclear plasma. Phosphorylation at Ser-187 by CDK2 occurs during late CC S-phase and results in dissociation from PCNA. {ECO:0000255|HAMAP- CC Rule:MF_03140, ECO:0000269|PubMed:20729856}. CC -!- PTM: Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation CC and increases interaction with PCNA. {ECO:0000255|HAMAP-Rule:MF_03140, CC ECO:0000269|PubMed:20729856}. CC -!- MISCELLANEOUS: [Isoform FENMIT]: No nuclease activity. Binds CC preferentially to RNA flap structures and R-loops. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the XPG/RAD2 endonuclease family. FEN1 CC subfamily. {ECO:0000255|HAMAP-Rule:MF_03140}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/fen1/"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40543/FEN1"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X76771; CAA54166.1; -; mRNA. DR EMBL; L37374; AAA91331.1; -; mRNA. DR EMBL; AF523117; AAM74238.1; -; Genomic_DNA. DR EMBL; AC004770; AAC23394.1; -; Genomic_DNA. DR EMBL; BC000323; AAH00323.1; -; mRNA. DR CCDS; CCDS8010.1; -. [P39748-1] DR PIR; A56531; A56531. DR RefSeq; NP_004102.1; NM_004111.5. [P39748-1] DR PDB; 1U7B; X-ray; 1.88 A; B=331-350. DR PDB; 1UL1; X-ray; 2.90 A; X/Y/Z=2-380. DR PDB; 3Q8K; X-ray; 2.20 A; A=2-336. DR PDB; 3Q8L; X-ray; 2.32 A; A=2-336. DR PDB; 3Q8M; X-ray; 2.60 A; A/B=2-336. DR PDB; 3UVU; X-ray; 2.38 A; B=352-370. DR PDB; 5E0V; X-ray; 2.07 A; C/D=335-350. DR PDB; 5FV7; X-ray; 2.84 A; A/B=1-336. DR PDB; 5K97; X-ray; 2.10 A; A=2-336. DR PDB; 5KSE; X-ray; 2.10 A; A=2-336. DR PDB; 5UM9; X-ray; 2.81 A; A=2-336. DR PDB; 5ZOD; X-ray; 1.90 A; A=1-333. DR PDB; 5ZOE; X-ray; 1.95 A; A=1-333. DR PDB; 5ZOF; X-ray; 2.25 A; A=1-333. DR PDB; 5ZOG; X-ray; 2.30 A; A=1-333. DR PDB; 6TNZ; EM; 4.05 A; H=1-380. DR PDB; 7QO1; EM; 4.40 A; Y=1-380. DR PDBsum; 1U7B; -. DR PDBsum; 1UL1; -. DR PDBsum; 3Q8K; -. DR PDBsum; 3Q8L; -. DR PDBsum; 3Q8M; -. DR PDBsum; 3UVU; -. DR PDBsum; 5E0V; -. DR PDBsum; 5FV7; -. DR PDBsum; 5K97; -. DR PDBsum; 5KSE; -. DR PDBsum; 5UM9; -. DR PDBsum; 5ZOD; -. DR PDBsum; 5ZOE; -. DR PDBsum; 5ZOF; -. DR PDBsum; 5ZOG; -. DR PDBsum; 6TNZ; -. DR PDBsum; 7QO1; -. DR AlphaFoldDB; P39748; -. DR EMDB; EMD-10540; -. DR EMDB; EMD-14080; -. DR EMDB; EMD-15385; -. DR SMR; P39748; -. DR BioGRID; 108528; 182. DR CORUM; P39748; -. DR DIP; DIP-24216N; -. DR ELM; P39748; -. DR IntAct; P39748; 51. DR MINT; P39748; -. DR STRING; 9606.ENSP00000305480; -. DR BindingDB; P39748; -. DR ChEMBL; CHEMBL5027; -. DR DrugBank; DB14490; Ferrous ascorbate. DR DrugBank; DB14491; Ferrous fumarate. DR DrugBank; DB14488; Ferrous gluconate. DR DrugBank; DB14501; Ferrous glycine sulfate. DR DrugBank; DB14489; Ferrous succinate. DR DrugBank; DB01592; Iron. DR GlyGen; P39748; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; P39748; -. DR MetOSite; P39748; -. DR PhosphoSitePlus; P39748; -. DR SwissPalm; P39748; -. DR BioMuta; FEN1; -. DR DMDM; 729475; -. DR CPTAC; CPTAC-1409; -. DR CPTAC; CPTAC-1410; -. DR CPTAC; CPTAC-1411; -. DR CPTAC; CPTAC-3230; -. DR CPTAC; CPTAC-700; -. DR EPD; P39748; -. DR jPOST; P39748; -. DR MassIVE; P39748; -. DR MaxQB; P39748; -. DR PaxDb; 9606-ENSP00000305480; -. DR PeptideAtlas; P39748; -. DR ProteomicsDB; 55319; -. [P39748-1] DR Pumba; P39748; -. DR TopDownProteomics; P39748-1; -. [P39748-1] DR ABCD; P39748; 1 sequenced antibody. DR Antibodypedia; 1878; 682 antibodies from 40 providers. DR CPTC; P39748; 1 antibody. DR DNASU; 2237; -. DR Ensembl; ENST00000305885.3; ENSP00000305480.2; ENSG00000168496.4. [P39748-1] DR GeneID; 2237; -. DR KEGG; hsa:2237; -. DR MANE-Select; ENST00000305885.3; ENSP00000305480.2; NM_004111.6; NP_004102.1. DR AGR; HGNC:3650; -. DR CTD; 2237; -. DR DisGeNET; 2237; -. DR GeneCards; FEN1; -. DR HGNC; HGNC:3650; FEN1. DR HPA; ENSG00000168496; Tissue enhanced (lymphoid). DR MIM; 600393; gene. DR neXtProt; NX_P39748; -. DR OpenTargets; ENSG00000168496; -. DR PharmGKB; PA28090; -. DR VEuPathDB; HostDB:ENSG00000168496; -. DR eggNOG; KOG2519; Eukaryota. DR GeneTree; ENSGT00940000155807; -. DR HOGENOM; CLU_032444_2_0_1; -. DR InParanoid; P39748; -. DR OMA; GSQDYDS; -. DR OrthoDB; 5479162at2759; -. DR PhylomeDB; P39748; -. DR TreeFam; TF105701; -. DR BRENDA; 3.1.99.B1; 2681. DR PathwayCommons; P39748; -. DR Reactome; R-HSA-110362; POLB-Dependent Long Patch Base Excision Repair. DR Reactome; R-HSA-162594; Early Phase of HIV Life Cycle. DR Reactome; R-HSA-174437; Removal of the Flap Intermediate from the C-strand. DR Reactome; R-HSA-5651801; PCNA-Dependent Long Patch Base Excision Repair. DR Reactome; R-HSA-5685939; HDR through MMEJ (alt-NHEJ). DR Reactome; R-HSA-69166; Removal of the Flap Intermediate. DR SignaLink; P39748; -. DR SIGNOR; P39748; -. DR BioGRID-ORCS; 2237; 542 hits in 1165 CRISPR screens. DR ChiTaRS; FEN1; human. DR EvolutionaryTrace; P39748; -. DR GeneWiki; Flap_structure-specific_endonuclease_1; -. DR GenomeRNAi; 2237; -. DR Pharos; P39748; Tchem. DR PRO; PR:P39748; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P39748; Protein. DR Bgee; ENSG00000168496; Expressed in endometrium epithelium and 193 other cell types or tissues. DR ExpressionAtlas; P39748; baseline and differential. DR GO; GO:0000781; C:chromosome, telomeric region; HDA:BHF-UCL. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0008409; F:5'-3' exonuclease activity; IDA:UniProtKB. DR GO; GO:0017108; F:5'-flap endonuclease activity; IDA:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; TAS:ProtInc. DR GO; GO:0003677; F:DNA binding; IMP:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; TAS:ProtInc. DR GO; GO:0008309; F:double-stranded DNA exodeoxyribonuclease activity; TAS:ProtInc. DR GO; GO:0004519; F:endonuclease activity; TAS:ProtInc. DR GO; GO:0004527; F:exonuclease activity; TAS:ProtInc. DR GO; GO:0048256; F:flap endonuclease activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IBA:GO_Central. DR GO; GO:0030145; F:manganese ion binding; IBA:GO_Central. DR GO; GO:0004523; F:RNA-DNA hybrid ribonuclease activity; IDA:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; TAS:Reactome. DR GO; GO:0006281; P:DNA repair; TAS:ProtInc. DR GO; GO:0006260; P:DNA replication; TAS:ProtInc. DR GO; GO:0043137; P:DNA replication, removal of RNA primer; IDA:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; TAS:ProtInc. DR GO; GO:0000724; P:double-strand break repair via homologous recombination; TAS:Reactome. DR GO; GO:0007613; P:memory; IEA:Ensembl. DR GO; GO:0090304; P:nucleic acid metabolic process; IDA:UniProtKB. DR GO; GO:0045876; P:positive regulation of sister chromatid cohesion; IMP:UniProtKB. DR GO; GO:0032201; P:telomere maintenance via semi-conservative replication; TAS:Reactome. DR GO; GO:0009650; P:UV protection; TAS:ProtInc. DR CDD; cd09907; H3TH_FEN1-Euk; 1. DR CDD; cd09867; PIN_FEN1; 1. DR DisProt; DP01974; -. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR Gene3D; 3.40.50.1010; 5'-nuclease; 1. DR HAMAP; MF_00614; Fen; 1. DR IDEAL; IID00044; -. DR InterPro; IPR036279; 5-3_exonuclease_C_sf. DR InterPro; IPR023426; Flap_endonuc. DR InterPro; IPR008918; HhH2. DR InterPro; IPR029060; PIN-like_dom_sf. DR InterPro; IPR006086; XPG-I_dom. DR InterPro; IPR006084; XPG/Rad2. DR InterPro; IPR019974; XPG_CS. DR InterPro; IPR006085; XPG_DNA_repair_N. DR PANTHER; PTHR11081:SF9; FLAP ENDONUCLEASE 1; 1. DR PANTHER; PTHR11081; FLAP ENDONUCLEASE FAMILY MEMBER; 1. DR Pfam; PF00867; XPG_I; 1. DR Pfam; PF00752; XPG_N; 1. DR PRINTS; PR00853; XPGRADSUPER. DR SMART; SM00279; HhH2; 1. DR SMART; SM00484; XPGI; 1. DR SMART; SM00485; XPGN; 1. DR SUPFAM; SSF47807; 5' to 3' exonuclease, C-terminal subdomain; 1. DR SUPFAM; SSF88723; PIN domain-like; 1. DR PROSITE; PS00841; XPG_1; 1. DR PROSITE; PS00842; XPG_2; 1. DR Genevisible; P39748; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative initiation; KW Direct protein sequencing; DNA damage; DNA repair; DNA replication; KW Endonuclease; Exonuclease; Hydrolase; Magnesium; Metal-binding; KW Methylation; Mitochondrion; Nuclease; Nucleus; Phosphoprotein; KW Reference proteome. FT CHAIN 1..380 FT /note="Flap endonuclease 1" FT /id="PRO_0000154069" FT REGION 1..104 FT /note="N-domain" FT REGION 122..253 FT /note="I-domain" FT REGION 327..380 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 336..344 FT /note="Interaction with PCNA" FT /evidence="ECO:0000269|PubMed:9305916" FT COMPBIAS 328..342 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 352..366 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 34 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:15616578, FT ECO:0007744|PDB:1UL1" FT BINDING 47 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT BINDING 70 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT BINDING 86 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:15616578, FT ECO:0007744|PDB:1UL1, ECO:0007744|PDB:5FV7" FT BINDING 158 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT BINDING 158 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:15616578, FT ECO:0007744|PDB:1UL1, ECO:0007744|PDB:5FV7" FT BINDING 160 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:15616578, FT ECO:0007744|PDB:1UL1, ECO:0007744|PDB:5FV7, FT ECO:0007744|PDB:5ZOD" FT BINDING 179 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /evidence="ECO:0007744|PDB:5FV7, ECO:0007744|PDB:5ZOD" FT BINDING 181 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:15616578, FT ECO:0007744|PDB:1UL1, ECO:0007744|PDB:5FV7, FT ECO:0007744|PDB:5ZOD" FT BINDING 231 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT BINDING 233 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT BINDING 233 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /evidence="ECO:0007744|PDB:5ZOD" FT MOD_RES 19 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:20729856" FT MOD_RES 80 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 100 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:20729856" FT MOD_RES 104 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:20729856" FT MOD_RES 187 FT /note="Phosphoserine; by CDK2" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:20729856" FT MOD_RES 192 FT /note="Symmetric dimethylarginine; by PRMT5" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:20729856" FT MOD_RES 197 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 255 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 293 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 335 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 336 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 354 FT /note="N6-acetyllysine" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:11430825" FT MOD_RES 364 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 375 FT /note="N6-acetyllysine" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:11430825, ECO:0007744|PubMed:19608861" FT MOD_RES 377 FT /note="N6-acetyllysine" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:11430825" FT MOD_RES 380 FT /note="N6-acetyllysine" FT /evidence="ECO:0000255|HAMAP-Rule:MF_03140, FT ECO:0000269|PubMed:11430825" FT VAR_SEQ 1..64 FT /note="Missing (in isoform FENMIT)" FT /evidence="ECO:0000305" FT /id="VSP_047520" FT MUTAGEN 29 FT /note="R->A: No significant effect on exonuclease activity FT or flap endonuclease activity." FT /evidence="ECO:0000269|PubMed:11986308" FT MUTAGEN 34 FT /note="D->A: Loss of flap endonuclease activity but FT substrate binding activity is retained." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 47 FT /note="R->A: Significantly reduced exonuclease activity and FT reduced substrate binding. The positions of the cleavage FT sites are also shifted." FT /evidence="ECO:0000269|PubMed:11986308" FT MUTAGEN 70 FT /note="R->A: Loss of exonuclease activity and reduced FT endonuclease activity. Reduced substrate binding." FT /evidence="ECO:0000269|PubMed:11986308" FT MUTAGEN 73 FT /note="R->A: No significant effect on exonuclease activity FT or flap endonuclease activity." FT /evidence="ECO:0000269|PubMed:11986308" FT MUTAGEN 80 FT /note="K->A: No significant effect on exonuclease activity FT or flap endonuclease activity." FT /evidence="ECO:0000269|PubMed:11986308" FT MUTAGEN 86 FT /note="D->A: Loss of flap endonuclease activity but FT substrate binding activity is retained." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 103 FT /note="R->A: No effect on flap endonuclease activity or FT substrate binding." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 158 FT /note="E->A: Loss of flap endonuclease activity and FT substrate binding." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 179 FT /note="D->A: No effect on flap endonuclease activity or FT substrate binding." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 181 FT /note="D->A: Loss of flap endonuclease activity but FT substrate binding activity is retained." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 187 FT /note="S->A: Fails to translocate from nucleoli to the FT nuclear plasma." FT /evidence="ECO:0000269|PubMed:18443037" FT MUTAGEN 187 FT /note="S->D: Diminishes nucleolar localization." FT /evidence="ECO:0000269|PubMed:18443037" FT MUTAGEN 192 FT /note="R->K: Impairs ability to localize to sites of DNA FT replication or repair." FT /evidence="ECO:0000269|PubMed:20729856" FT MUTAGEN 231 FT /note="G->A: Loss of flap endonuclease activity and FT substrate binding." FT /evidence="ECO:0000269|PubMed:8621570" FT MUTAGEN 233 FT /note="D->A: Loss of flap endonuclease activity and FT substrate binding." FT /evidence="ECO:0000269|PubMed:8621570" FT HELIX 6..13 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 15..17 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 18..21 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 23..26 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 30..34 FT /evidence="ECO:0007829|PDB:5ZOD" FT TURN 35..37 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 46..48 FT /evidence="ECO:0007829|PDB:5ZOE" FT HELIX 64..76 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 80..85 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 91..93 FT /evidence="ECO:0007829|PDB:5K97" FT HELIX 94..116 FT /evidence="ECO:0007829|PDB:5K97" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:5K97" FT HELIX 123..129 FT /evidence="ECO:0007829|PDB:5K97" FT HELIX 139..148 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 152..154 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 159..168 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 171..176 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 181..184 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 188..193 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 198..200 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 204..208 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 209..216 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 220..230 FT /evidence="ECO:0007829|PDB:5ZOD" FT STRAND 232..235 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 243..253 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 256..262 FT /evidence="ECO:0007829|PDB:5ZOD" FT TURN 265..267 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 276..284 FT /evidence="ECO:0007829|PDB:5ZOD" FT TURN 291..293 FT /evidence="ECO:0007829|PDB:5ZOE" FT HELIX 303..311 FT /evidence="ECO:0007829|PDB:5ZOD" FT TURN 312..314 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 318..330 FT /evidence="ECO:0007829|PDB:5ZOD" FT HELIX 340..342 FT /evidence="ECO:0007829|PDB:1U7B" FT STRAND 344..351 FT /evidence="ECO:0007829|PDB:1UL1" SQ SEQUENCE 380 AA; 42593 MW; 5154F2F6E57592C5 CRC64; MGIQGLAKLI ADVAPSAIRE NDIKSYFGRK VAIDASMSIY QFLIAVRQGG DVLQNEEGET TSHLMGMFYR TIRMMENGIK PVYVFDGKPP QLKSGELAKR SERRAEAEKQ LQQAQAAGAE QEVEKFTKRL VKVTKQHNDE CKHLLSLMGI PYLDAPSEAE ASCAALVKAG KVYAAATEDM DCLTFGSPVL MRHLTASEAK KLPIQEFHLS RILQELGLNQ EQFVDLCILL GSDYCESIRG IGPKRAVDLI QKHKSIEEIV RRLDPNKYPV PENWLHKEAH QLFLEPEVLD PESVELKWSE PNEEELIKFM CGEKQFSEER IRSGVKRLSK SRQGSTQGRL DDFFKVTGSL SSAKRKEPEP KGSTKKKAKT GAAGKFKRGK //