Flap endonuclease 1

Details

Name
Flap endonuclease 1
Synonyms
  • 3.1.-.-
  • DNase IV
  • FEN-1
  • Flap structure-specific endonuclease 1
  • hFEN-1
  • Maturation factor 1
  • MF1
  • RAD2
Gene Name
FEN1
Organism
Humans
Amino acid sequence
>lcl|BSEQ0049739|Flap endonuclease 1
MGIQGLAKLIADVAPSAIRENDIKSYFGRKVAIDASMSIYQFLIAVRQGGDVLQNEEGET
TSHLMGMFYRTIRMMENGIKPVYVFDGKPPQLKSGELAKRSERRAEAEKQLQQAQAAGAE
QEVEKFTKRLVKVTKQHNDECKHLLSLMGIPYLDAPSEAEASCAALVKAGKVYAAATEDM
DCLTFGSPVLMRHLTASEAKKLPIQEFHLSRILQELGLNQEQFVDLCILLGSDYCESIRG
IGPKRAVDLIQKHKSIEEIVRRLDPNKYPVPENWLHKEAHQLFLEPEVLDPESVELKWSE
PNEEELIKFMCGEKQFSEERIRSGVKRLSKSRQGSTQGRLDDFFKVTGSLSSAKRKEPEP
KGSTKKKAKTGAAGKFKRGK
Number of residues
380
Molecular Weight
42592.635
Theoretical pI
Not Available
GO Classification
Functions
5'-3' exonuclease activity / 5'-flap endonuclease activity / damaged DNA binding / DNA binding / double-stranded DNA binding / double-stranded DNA exodeoxyribonuclease activity / endonuclease activity / exonuclease activity / flap endonuclease activity / metal ion binding / RNA-DNA hybrid ribonuclease activity
Processes
DNA repair / DNA replication / DNA replication, removal of RNA primer / double-strand break repair / double-strand break repair via homologous recombination / memory / nucleic acid phosphodiester bond hydrolysis / positive regulation of sister chromatid cohesion / telomere maintenance via recombination / UV protection
Components
membrane / mitochondrion / nuclear chromosome, telomeric region / nucleolus / nucleoplasm / nucleus / protein complex
General Function
Structure-specific nuclease with 5'-flap endonuclease and 5'-3' exonuclease activities involved in DNA replication and repair. During DNA replication, cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. It enters the flap from the 5'-end and then tracks to cleave the flap base, leaving a nick for ligation. Also involved in the long patch base excision repair (LP-BER) pathway, by cleaving within the apurinic/apyrimidinic (AP) site-terminated flap. Acts as a genome stabilization factor that prevents flaps from equilibrating into structurs that lead to duplications and deletions. Also possesses 5'-3' exonuclease activity on nicked or gapped double-stranded DNA, and exhibits RNase H activity. Also involved in replication and repair of rDNA and in repairing mitochondrial DNA.
Specific Function
5'-3' exonuclease activity
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0049740|Flap endonuclease 1 (FEN1)
ATGGGAATTCAAGGCCTGGCCAAACTAATTGCTGATGTGGCCCCCAGTGCCATCCGGGAG
AATGACATCAAGAGCTACTTTGGCCGTAAGGTGGCCATTGATGCCTCTATGAGCATTTAT
CAGTTCCTGATTGCTGTTCGCCAGGGTGGGGATGTGCTGCAGAATGAGGAGGGTGAGACC
ACCAGCCACCTGATGGGCATGTTCTACCGCACCATTCGCATGATGGAGAACGGCATCAAG
CCCGTGTATGTCTTTGATGGCAAGCCGCCACAGCTCAAGTCAGGCGAGCTGGCCAAACGC
AGTGAGCGGCGGGCTGAGGCAGAGAAGCAGCTGCAGCAGGCTCAGGCTGCTGGGGCCGAG
CAGGAGGTGGAAAAATTCACTAAGCGGCTGGTGAAGGTCACTAAGCAGCACAATGATGAG
TGCAAACATCTGCTGAGCCTCATGGGCATCCCTTATCTTGATGCACCCAGTGAGGCAGAG
GCCAGCTGTGCTGCCCTGGTGAAGGCTGGCAAAGTCTATGCTGCGGCTACCGAGGACATG
GACTGCCTCACCTTCGGCAGCCCTGTGCTAATGCGACACCTGACTGCCAGTGAAGCCAAA
AAGCTGCCAATCCAGGAATTCCACCTGAGCCGGATTCTGCAGGAGCTGGGCCTGAACCAG
GAACAGTTTGTGGATCTGTGCATCCTGCTAGGCAGTGACTACTGTGAGAGTATCCGGGGT
ATTGGGCCCAAGCGGGCTGTGGACCTCATCCAGAAGCACAAGAGCATCGAGGAGATCGTG
CGGCGACTTGACCCCAACAAGTACCCTGTGCCAGAAAATTGGCTCCACAAGGAGGCTCAC
CAGCTCTTCTTGGAACCTGAGGTGCTGGACCCAGAGTCTGTGGAGCTGAAGTGGAGCGAG
CCAAATGAAGAAGAGCTGATCAAGTTCATGTGTGGTGAAAAGCAGTTCTCTGAGGAGCGA
ATCCGCAGTGGGGTCAAGAGGCTGAGTAAGAGCCGCCAAGGCAGCACCCAGGGCCGCCTG
GATGATTTCTTCAAGGTGACCGGCTCACTCTCTTCAGCTAAGCGCAAGGAGCCAGAACCC
AAGGGATCCACTAAGAAGAAGGCAAAGACTGGGGCAGCAGGGAAGTTTAAAAGGGGAAAA
TAA
Chromosome Location
11
Locus
11q12.2
External Identifiers
ResourceLink
UniProtKB IDP39748
UniProtKB Entry NameFEN1_HUMAN
HGNC IDHGNC:3650
General References
  1. Murray JM, Tavassoli M, al-Harithy R, Sheldrick KS, Lehmann AR, Carr AM, Watts FZ: Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage. Mol Cell Biol. 1994 Jul;14(7):4878-88. [PubMed:8007985]
  2. Hiraoka LR, Harrington JJ, Gerhard DS, Lieber MR, Hsieh CL: Sequence of human FEN-1, a structure-specific endonuclease, and chromosomal localization of the gene (FEN1) in mouse and human. Genomics. 1995 Jan 1;25(1):220-5. [PubMed:7774922]
  3. Taylor TD, Noguchi H, Totoki Y, Toyoda A, Kuroki Y, Dewar K, Lloyd C, Itoh T, Takeda T, Kim DW, She X, Barlow KF, Bloom T, Bruford E, Chang JL, Cuomo CA, Eichler E, FitzGerald MG, Jaffe DB, LaButti K, Nicol R, Park HS, Seaman C, Sougnez C, Yang X, Zimmer AR, Zody MC, Birren BW, Nusbaum C, Fujiyama A, Hattori M, Rogers J, Lander ES, Sakaki Y: Human chromosome 11 DNA sequence and analysis including novel gene identification. Nature. 2006 Mar 23;440(7083):497-500. [PubMed:16554811]
  4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  5. Robins P, Pappin DJ, Wood RD, Lindahl T: Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I. J Biol Chem. 1994 Nov 18;269(46):28535-8. [PubMed:7961795]
  6. Shen B, Nolan JP, Sklar LA, Park MS: Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J Biol Chem. 1996 Apr 19;271(16):9173-6. [PubMed:8621570]
  7. Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS: The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. J Biol Chem. 1997 Sep 26;272(39):24522-9. [PubMed:9305916]
  8. Tom S, Henricksen LA, Bambara RA: Mechanism whereby proliferating cell nuclear antigen stimulates flap endonuclease 1. J Biol Chem. 2000 Apr 7;275(14):10498-505. [PubMed:10744741]
  9. Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hubscher U, Hottiger MO: Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300. Mol Cell. 2001 Jun;7(6):1221-31. [PubMed:11430825]
  10. Qiu J, Bimston DN, Partikian A, Shen B: Arginine residues 47 and 70 of human flap endonuclease-1 are involved in DNA substrate interactions and cleavage site determination. J Biol Chem. 2002 Jul 5;277(27):24659-66. Epub 2002 May 1. [PubMed:11986308]
  11. Farina A, Shin JH, Kim DH, Bermudez VP, Kelman Z, Seo YS, Hurwitz J: Studies with the human cohesin establishment factor, ChlR1. Association of ChlR1 with Ctf18-RFC and Fen1. J Biol Chem. 2008 Jul 25;283(30):20925-36. doi: 10.1074/jbc.M802696200. Epub 2008 May 21. [PubMed:18499658]
  12. Guo Z, Qian L, Liu R, Dai H, Zhou M, Zheng L, Shen B: Nucleolar localization and dynamic roles of flap endonuclease 1 in ribosomal DNA replication and damage repair. Mol Cell Biol. 2008 Jul;28(13):4310-9. doi: 10.1128/MCB.00200-08. Epub 2008 Apr 28. [PubMed:18443037]
  13. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. [PubMed:19608861]
  14. Guo Z, Zheng L, Xu H, Dai H, Zhou M, Pascua MR, Chen QM, Shen B: Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat Chem Biol. 2010 Oct;6(10):766-73. doi: 10.1038/nchembio.422. Epub 2010 Aug 22. [PubMed:20729856]
  15. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [PubMed:20068231]
  16. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [PubMed:21269460]
  17. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [PubMed:22814378]
  18. Zhou H, Di Palma S, Preisinger C, Peng M, Polat AN, Heck AJ, Mohammed S: Toward a comprehensive characterization of a human cancer cell phosphoproteome. J Proteome Res. 2013 Jan 4;12(1):260-71. doi: 10.1021/pr300630k. Epub 2012 Dec 18. [PubMed:23186163]
  19. Kazak L, Reyes A, He J, Wood SR, Brea-Calvo G, Holen TT, Holt IJ: A cryptic targeting signal creates a mitochondrial FEN1 isoform with tailed R-Loop binding properties. PLoS One. 2013 May 13;8(5):e62340. doi: 10.1371/journal.pone.0062340. Print 2013. [PubMed:23675412]
  20. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [PubMed:24275569]
  21. Bruning JB, Shamoo Y: Structural and thermodynamic analysis of human PCNA with peptides derived from DNA polymerase-delta p66 subunit and flap endonuclease-1. Structure. 2004 Dec;12(12):2209-19. [PubMed:15576034]
  22. Sakurai S, Kitano K, Yamaguchi H, Hamada K, Okada K, Fukuda K, Uchida M, Ohtsuka E, Morioka H, Hakoshima T: Structural basis for recruitment of human flap endonuclease 1 to PCNA. EMBO J. 2005 Feb 23;24(4):683-93. Epub 2004 Dec 16. [PubMed:15616578]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB01592IronapprovedunknownDetails
DB14488Ferrous gluconateapprovedunknownDetails
DB14489Ferrous succinateapprovedunknownDetails
DB14490Ferrous ascorbateapprovedunknownDetails
DB14491Ferrous fumarateapprovedunknownDetails
DB14501Ferrous glycine sulfateapprovedunknownDetails