Fen1
5’ flap endonuclease involved in processing Okazaki fragments.
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Synonyms |
•Rad27, ercII, MF1
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Molecular weight |
•45-55kDa |
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Biochemical properties |
•55kDa 5-3 ds specific endonuclease (1) prefers branched (flapped) substrates (2) |
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Motifs |
•NLS (3) •PCNA binding motif QGRLDDFFK (4) |
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Protein interactions |
Sc •PCNA (5) •DNA2 (6) •Elg1 (Rfc-1-like subunit) (7)
Mammals •PCNA (8) •WRN helicase (9) •Condensin? (10)
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Modifications |
•Phosphorylation (11) |
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Structure |
• x-ray structure fen interaction with pcna (12) , (13) (14) and archael (15) •em structure pcna fen (16) |
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Cellular location and expression |
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Other comments |
Sc •needed to maintain long track repeats (17)
Mammals •Exonuclease in DNA replication and endonuclease in repair (13) nuclease needed to suppress mutations (18) • Likely role in repair - mms (19) nhej - (20) • inhibited by rpa (21) •stimulated by wrn (22) (9) • strong mutator phenotype (23) • premature aging (24) • role in trinucleotide repeat expansion (25)
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Adopted by |
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Last edited |
13 April 08 |
1. Turchi,J.J. and Bambara,R.A. (1993) Completion of mammalian lagging strand DNA replication using purified proteins. J Biol Chem 268, 15136-15141.
2. Li,X., Li,J., Harrington,J., Lieber,M.R. and Burgers,P.M. (1995) Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen. J Biol Chem270, 22109-22112.
3. Qiu,J., Li,X., Frank,G. and Shen,B. (2001) Cell cycle-dependent and DNA damage-inducible nuclear localization of FEN-1 nuclease is consistent with its dual functions in DNA replication and repair. J Biol Chem 276, 4901-4908.
4. Zheng,L., Dai,H., Qiu,J., Huang,Q. and Shen,B. (2007) Disruption of the FEN-1/PCNA interaction results in DNA replication defects, pulmonary hypoplasia, pancytopenia, and newborn lethality in mice. Mol Cell Biol 27, 3176-3186.
5. Gomes,X.V. and Burgers,P.M. (2001) ATP utilization by yeast replication factor C. I. ATP-mediated interaction with DNA and with proliferating cell nuclear antigen. J Biol Chem 276, 34768-34775.
6. Budd,M.E. and Campbell,J.L. (1997) A yeast replicative helicase, Dna2 helicase, interacts with yeast FEN-1 nuclease in carrying out its essential function. Mol Cell Biol 17, 2136-2142.
7. Kanellis,P., Agyei,R. and Durocher,D. (2003) Elg1 forms an alternative PCNA-interacting RFC complex required to maintain genome stability. Curr Biol13, 1583-1595.
8. Wu,X., Li,J., Li,X., Hsieh,C.L., Burgers,P.M. and Lieber,M.R. (1996) Processing of branched DNA intermediates by a complex of human FEN-1 and PCNA. Nucleic Acids Res 24, 2036-2043.
9. Sharma,S., Otterlei,M., Sommers,J.A., Driscoll,H.C., Dianov,G.L., Kao,H.I., Bambara,R.A. and Brosh,R.M.J. (2004) WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork. Mol Biol Cell 15, 734-750.
10. Heale,J.T., Ball,A.R.J., Schmiesing,J.A., Kim,J.S., Kong,X., Zhou,S., Hudson,D.F., Earnshaw,W.C. and Yokomori,K. (2006) Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair. Mol Cell21, 837-848.
11. Henneke,G., Koundrioukoff,S. and Hubscher,U. (2003) Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. Oncogene 22, 4301-4313.
12. Chapados,B.R., Hosfield,D.J., Han,S., Qiu,J., Yelent,B., Shen,B. and Tainer,J.A. (2004) Structural basis for FEN-1 substrate specificity and PCNA-mediated activation in DNA replication and repair. Cell 116, 39-50.
13. Hosfield,D.J., Mol,C.D., Shen,B. and Tainer,J.A. (1998) Structure of the DNA repair and replication endonuclease and exonuclease FEN-1: coupling DNA and PCNA binding to FEN-1 activity. Cell 95, 135-146.
14. Sakurai,S., Kitano,K., Yamaguchi,H., Hamada,K., Okada,K., Fukuda,K., Uchida,M., Ohtsuka,E., Morioka,H. and Hakoshima,T. (2005) Structural basis for recruitment of human flap endonuclease 1 to PCNA. EMBO J 24, 683-693.
15. Dore,A.S., Kilkenny,M.L., Jones,S.A., Oliver,A.W., Roe,S.M., Bell,S.D. and Pearl,L.H. (2006) Structure of an archaeal PCNA1-PCNA2-FEN1 complex: elucidating PCNA subunit and client enzyme specificity. Nucleic Acids Res 34, 4515-4526.
16. Trakselis,M.A. and Bell,S.D. (2004) Molecular biology: the loader of the rings. Nature 429, 708-709.
17. Yang,J. and Freudenreich,C.H. (2007) Haploinsufficiency of yeast FEN1 causes instability of expanded CAG/CTG tracts in a length-dependent manner. Gene 393, 110-115.
18. Zheng,L., Dai,H., Zhou,M., Li,M., Singh,P., Qiu,J., Tsark,W., Huang,Q., Kernstine,K., Zhang,X., Lin,D. and Shen,B. (2007) Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nat Med 13, 812-819.
19. Shibata,Y. and Nakamura,T. (2002) Defective flap endonuclease 1 activity in mammalian cells is associated with impaired DNA repair and prolonged S phase delay. J Biol Chem 277, 746-754.
20. Wu,X., Wilson,T.E. and Lieber,M.R. (1999) A role for FEN-1 in nonhomologous DNA end joining: the order of strand annealing and nucleolytic processing events. Proc Natl Acad Sci U S A 96, 1303-1308.
21. Bae,S.H., Bae,K.H., Kim,J.A. and Seo,Y.S. (2001) RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature 412, 456-461.
22. Sharma,S., Sommers,J.A., Gary,R.K., Friedrich-Heineken,E., Hubscher,U. and Brosh,R.M.J. (2005) The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic Acids Res 33, 6769-6781.
23. Shen,B., Qiu,J., Hosfield,D. and Tainer,J.A. (1998) Flap endonuclease homologs in archaebacteria exist as independent proteins. Trends Biochem Sci 23, 171-173.
24. Hoopes,L.L., Budd,M., Choe,W., Weitao,T. and Campbell,J.L. (2002) Mutations in DNA replication genes reduce yeast life span. Mol Cell Biol 22, 4136-4146.
25. Singh,P., Zheng,L., Chavez,V., Qiu,J. and Shen,B. (2007) Concerted action of exonuclease and Gap-dependent endonuclease activities of FEN-1 contributes to the resolution of triplet repeat sequences (CTG)n- and (GAA)n-derived secondary structures formed during maturation of Okazaki fragments. J Biol Chem282, 3465-3477.