5’ flap endonuclease involved in processing Okazaki fragments.




•Rad27, ercII, MF1


Molecular weight


Biochemical properties

•55kDa 5-3 ds specific endonuclease (1) prefers branched (flapped) substrates (2)


•NLS (3)

•PCNA binding motif QGRLDDFFK (4)

Protein interactions


•PCNA (5)

•DNA2 (6)

•Elg1 (Rfc-1-like subunit) (7)



•PCNA  (8)

•WRN helicase  (9)

•Condensin? (10)



•Phosphorylation (11)


 • x-ray structure fen interaction with pcna (12) , (13) (14) and archael (15)

•em structure pcna fen (16)

Cellular location and expression


Other comments


•needed to maintain long track repeats (17)



•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)



Adopted by


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.