UniProt Accession

 FEN1_HUMAN; P39748 

Genbank Protein ID

 X76771; L37374; AF523117; AC004770; BC000323 

Genbank Nucleotide ID

 CAA54166.1; AAA91331.1; AAM74238.1; AAC23394.1; AAH00323.1 

Protein Name

 Flap endonuclease 1 

Protein Synonyms/Alias

 FEN-1; DNase IV; Flap structure-specific endonuclease 1; Maturation factor 1; MF1; hFEN-1 

Gene Name

 FEN1 

Gene Synonyms/Alias

 RAD2 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
8	MGIQGLAKLIADVAP	ubiquitination	[1, 2, 3]
24	AIRENDIKSYFGRKV	ubiquitination	[2]
80	RMMENGIKPVYVFDG	acetylation	[4]
80	RMMENGIKPVYVFDG	ubiquitination	[2]
88	PVYVFDGKPPQLKSG	ubiquitination	[2]
109	ERRAEAEKQLQQAQA	ubiquitination	[2, 5, 6]
125	GAEQEVEKFTKRLVK	ubiquitination	[1, 2, 3, 5]
128	QEVEKFTKRLVKVTK	ubiquitination	[2]
171	AALVKAGKVYAAATE	ubiquitination	[2]
200	HLTASEAKKLPIQEF	acetylation	[7, 8]
201	LTASEAKKLPIQEFH	ubiquitination	[2]
252	RAVDLIQKHKSIEEI	ubiquitination	[2]
254	VDLIQKHKSIEEIVR	ubiquitination	[2, 6]
267	VRRLDPNKYPVPENW	acetylation	[4]
267	VRRLDPNKYPVPENW	ubiquitination	[2]
277	VPENWLHKEAHQLFL	ubiquitination	[5]
297	DPESVELKWSEPNEE	ubiquitination	[5]
314	IKFMCGEKQFSEERI	ubiquitination	[2, 9, 10]
345	GRLDDFFKVTGSLSS	ubiquitination	[2, 10]
354	TGSLSSAKRKEPEPK	acetylation	[11, 12, 13]
354	TGSLSSAKRKEPEPK	ubiquitination	[2]
375	AKTGAAGKFKRGK**	acetylation	[4, 8, 11, 12, 14]
377	TGAAGKFKRGK****	acetylation	[11, 12, 14]
380	AGKFKRGK*******	acetylation	[11, 12]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [4] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861]
 [5] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [6] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [7] Proteomic investigations of lysine acetylation identify diverse substrates of mitochondrial deacetylase sirt3.
 Sol EM, Wagner SA, Weinert BT, Kumar A, Kim HS, Deng CX, Choudhary C.
 PLoS One. 2012;7(12):e50545. [PMID: 23236377]
 [8] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302]
 [9] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [10] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
 [11] Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300.
 Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO.
 Mol Cell. 2001 Jun;7(6):1221-31. [PMID: 11430825]
 [12] The acetylatable lysines of human Fen1 are important for endo- and exonuclease activities.
 Friedrich-Heineken E, Henneke G, Ferrari E, Hübscher U.
 J Mol Biol. 2003 Apr 18;328(1):73-84. [PMID: 12683998]
 [13] Regulation of cellular metabolism by protein lysine acetylation.
 Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL.
 Science. 2010 Feb 19;327(5968):1000-4. [PMID: 20167786]
 [14] Monoclonal antibody cocktail as an enrichment tool for acetylome analysis.
 Shaw PG, Chaerkady R, Zhang Z, Davidson NE, Pandey A.
 Anal Chem. 2011 May 15;83(10):3623-6. [PMID: 21466224] 

Functional Description

 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. 

Sequence Annotation

 REGION 1 104 N-domain.
 REGION 122 253 I-domain.
 REGION 336 344 Interaction with PCNA.
 METAL 34 34 Magnesium 1.
 METAL 86 86 Magnesium 1.
 METAL 158 158 Magnesium 1.
 METAL 160 160 Magnesium 1.
 METAL 179 179 Magnesium 2.
 METAL 181 181 Magnesium 2.
 METAL 233 233 Magnesium 2.
 BINDING 47 47 DNA substrate.
 BINDING 70 70 DNA substrate.
 BINDING 158 158 DNA substrate.
 BINDING 231 231 DNA substrate.
 BINDING 233 233 DNA substrate.
 MOD_RES 19 19 Symmetric dimethylarginine; by PRMT5.
 MOD_RES 80 80 N6-acetyllysine.
 MOD_RES 100 100 Symmetric dimethylarginine; by PRMT5.
 MOD_RES 104 104 Symmetric dimethylarginine; by PRMT5.
 MOD_RES 187 187 Phosphoserine; by CDK2.
 MOD_RES 192 192 Symmetric dimethylarginine; by PRMT5.
 MOD_RES 197 197 Phosphoserine.
 MOD_RES 354 354 N6-acetyllysine.
 MOD_RES 364 364 Phosphothreonine.
 MOD_RES 375 375 N6-acetyllysine.
 MOD_RES 377 377 N6-acetyllysine.
 MOD_RES 380 380 N6-acetyllysine.  

Keyword

 3D-structure; Acetylation; Alternative initiation; Complete proteome; Direct protein sequencing; DNA damage; DNA repair; DNA replication; Endonuclease; Exonuclease; Hydrolase; Magnesium; Metal-binding; Methylation; Mitochondrion; Nuclease; Nucleus; Phosphoprotein; Reference proteome. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 380 AA 

Protein Sequence

Gene Ontology

 GO:0005739; C:mitochondrion; IDA:UniProtKB.
 GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0008409; F:5'-3' exonuclease activity; IDA:UniProtKB.
 GO:0017108; F:5'-flap endonuclease activity; IDA:UniProtKB.
 GO:0003684; F:damaged DNA binding; TAS:ProtInc.
 GO:0003690; F:double-stranded DNA binding; TAS:ProtInc.
 GO:0008309; F:double-stranded DNA specific exodeoxyribonuclease activity; TAS:ProtInc.
 GO:0000287; F:magnesium ion binding; IEA:HAMAP.
 GO:0030145; F:manganese ion binding; IEA:Compara.
 GO:0004523; F:ribonuclease H activity; IDA:UniProtKB.
 GO:0006284; P:base-excision repair; TAS:Reactome.
 GO:0043137; P:DNA replication, removal of RNA primer; IDA:UniProtKB.
 GO:0006302; P:double-strand break repair; TAS:ProtInc.
 GO:0007613; P:memory; IEA:Compara.
 GO:0000278; P:mitotic cell cycle; TAS:Reactome.
 GO:0048015; P:phosphatidylinositol-mediated signaling; NAS:UniProtKB.
 GO:0000722; P:telomere maintenance via recombination; TAS:Reactome.
 GO:0032201; P:telomere maintenance via semi-conservative replication; TAS:Reactome.
 GO:0009650; P:UV protection; TAS:ProtInc. 

Interpro

 IPR020045; 5-3_exonuclease_C.
 IPR023426; Flap_endonuc.
 IPR008918; HhH2.
 IPR006086; XPG-I_dom.
 IPR006084; XPG/Rad2.
 IPR019974; XPG_CS.
 IPR006085; XPG_DNA_repair_N. 

Pfam

 PF00867; XPG_I
 PF00752; XPG_N 

SMART

 SM00279; HhH2
 SM00484; XPGI
 SM00485; XPGN 

PROSITE

 PS00841; XPG_1
 PS00842; XPG_2 

PRINTS

 PR00853; XPGRADSUPER.