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Gene Review

FEN1  -  flap structure-specific endonuclease 1

Homo sapiens

Synonyms: DNase IV, FEN-1, Flap endonuclease 1, Flap structure-specific endonuclease 1, MF1, ...
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Disease relevance of FEN1


Psychiatry related information on FEN1

  • Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice [5].

High impact information on FEN1

  • Similarly, in long-patch base excision repair, a damaged nucleotide is displaced into a flap and removed by FEN1 [6].
  • FEN1 is a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions [6].
  • The conserved FEN-1 C terminus binds proliferating cell nuclear antigen (PCNA) and positions FEN-1 to act primarily as an exonuclease in DNA replication, in contrast to its endonuclease activity in DNA repair [7].
  • The enzyme's active-site structure suggests that DNA binding induces FEN-1 to clamp onto the cleavage junction to form the productive complex [7].
  • FEN-1 mutations altering PCNA binding should reduce activity during replication, likely causing DNA repeat expansions as seen in some cancers and genetic diseases [7].

Chemical compound and disease context of FEN1


Biological context of FEN1


Anatomical context of FEN1

  • FEN1 protein was abundantly expressed in all 23 lung cancer cell lines (10 SCLCs and 13 NSCLCs) and was expressed at lower levels in three of four normal lung epithelial culture controls [2].
  • In addition, microarray analysis showed that FEN1 expression was elevated significantly by 1.65-fold (P=0.001) in SCLC cell lines compared to normal lung controls (normal human lung cultures and immortalized normal human bronchial epithelial cell lines) [2].
  • A physical interaction between WRN and FEN-1 is demonstrated by their co-immunoprecipitation from HeLa cell lysate and affinity pull-down experiments using a recombinant C-terminal fragment of WRN [16].
  • Here, we demonstrate by immunodepletion experiments that 5'-dRP-N(3) excision in long patch BER of uracil-DNA in a human lymphoid cell extract is, indeed, dependent upon FEN1 [17].
  • This antibody has been used to examine Fen1 levels by immunoblotting and its subcellular localization in cultured cells and tissue samples by immunostaining [18].

Associations of FEN1 with chemical compounds

  • However once the THF residue was displaced at least a single nucleotide, stimulation of FEN1 activity by APE1 resumes [19].
  • After methyl methanesulfonate (MMS) damage, the mobile fraction of focal GFP-Fen1 decreased and t(m) increased, but it then recovered [20].
  • Both the 5' to 3' exonuclease and flap endonuclease activities require a divalent metal cofactor, with Mg(2+) being the preferred metal ion [21].
  • MMS treatment caused a prolonged delay of S phase progression and impairment in colony-forming activity of cells expressing nuclease-defective FEN-1 [22].
  • 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 [23].

Physical interactions of FEN1


Enzymatic interactions of FEN1


Co-localisations of FEN1


Regulatory relationships of FEN1

  • Furthermore, APE1 was able to enhance overall product formation in reconstitution of BER steps involving FEN1 cleavage followed by ligation [19].
  • The human Rad9-Rad1-Hus1 checkpoint complex stimulates flap endonuclease 1 [13].
  • WRN retained its ability to physically bind and stimulate acetylated FEN-1 cleavage activity to the same extent as unacetylated FEN-1 [26].
  • BLM helicase activity could directly disrupt annealing at the ectopic site and promote flap endonuclease-1 cleavage [27].

Other interactions of FEN1


Analytical, diagnostic and therapeutic context of FEN1


  1. 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. Gary, R., Ludwig, D.L., Cornelius, H.L., MacInnes, M.A., Park, M.S. J. Biol. Chem. (1997) [Pubmed]
  2. Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer. Sato, M., Girard, L., Sekine, I., Sunaga, N., Ramirez, R.D., Kamibayashi, C., Minna, J.D. Oncogene (2003) [Pubmed]
  3. Stimulation of human flap endonuclease 1 by human immunodeficiency virus type 1 integrase: possible role for flap endonuclease 1 in 5'-end processing of human immunodeficiency virus type 1 integration intermediates. Faust, E.A., Triller, H. J. Biomed. Sci. (2002) [Pubmed]
  4. Distant structural homology leads to the functional characterization of an archaeal PIN domain as an exonuclease. Arcus, V.L., Bäckbro, K., Roos, A., Daniel, E.L., Baker, E.N. J. Biol. Chem. (2004) [Pubmed]
  5. Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability. Spiro, C., McMurray, C.T. Mol. Cell. Biol. (2003) [Pubmed]
  6. Flap endonuclease 1: a central component of DNA metabolism. Liu, Y., Kao, H.I., Bambara, R.A. Annu. Rev. Biochem. (2004) [Pubmed]
  7. Structure of the DNA repair and replication endonuclease and exonuclease FEN-1: coupling DNA and PCNA binding to FEN-1 activity. Hosfield, D.J., Mol, C.D., Shen, B., Tainer, J.A. Cell (1998) [Pubmed]
  8. Detection and purification of a novel 72 kDa glycoprotein male breast tumor associated antigen. Basu, A., Basu, I., Chakraborty, A., Pal, S., Chattopadhyay, U. Int. J. Cancer (2003) [Pubmed]
  9. Differential recognition of microfilarial chitinase, a transmission-blocking vaccine candidate antigen, by sera from patients with Brugian and Bancroftian filariasis. Dissanayake, S., Perler, F.B., Xu, M., Southworth, M.W., Yee, C.K., Wang, S., Dreyer, G., Watawana, L., Kurniawan, L., Fuhrman, J.A. Am. J. Trop. Med. Hyg. (1995) [Pubmed]
  10. Formaldehyde-limited cultivation of a newly isolated methylotrophic bacterium, Methylobacterium sp. MF1: enzymatic analysis related to C1 metabolism. Mitsui, R., Omori, M., Kitazawa, H., Tanaka, M. J. Biosci. Bioeng. (2005) [Pubmed]
  11. Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis. Michiels, J.J., Kutti, J., Stark, P., Bazzan, M., Gugliotta, L., Marchioli, R., Griesshammer, M., van Genderen, P.J., Brière, J., Kiladjian, J.J., Barbui, T., Finazzi, G., Berlin, N.I., Pearson, T.C., Green, A.C., Fruchtmann, S.M., Silver, R.T., Hansmann, E., Wehmeier, A., Lengfelder, E., Landolfi, R., Kvasnicka, H.M., Hasselbalch, H., Cervantes, F., Thiele, J. The Netherlands journal of medicine. (1999) [Pubmed]
  12. Structural basis for recruitment of human flap endonuclease 1 to PCNA. Sakurai, S., Kitano, K., Yamaguchi, H., Hamada, K., Okada, K., Fukuda, K., Uchida, M., Ohtsuka, E., Morioka, H., Hakoshima, T. EMBO J. (2005) [Pubmed]
  13. The human Rad9-Rad1-Hus1 checkpoint complex stimulates flap endonuclease 1. Wang, W., Brandt, P., Rossi, M.L., Lindsey-Boltz, L., Podust, V., Fanning, E., Sancar, A., Bambara, R.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  14. Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes. Ma, X., Jin, Q., Försti, A., Hemminki, K., Kumar, R. Int. J. Cancer (2000) [Pubmed]
  15. Two overlapping divergent transcription units in the human genome: the FEN1/C11orf10 locus. Adachi, N., Karanjawala, Z.E., Matsuzaki, Y., Koyama, H., Lieber, M.R. OMICS (2002) [Pubmed]
  16. Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity. Brosh, R.M., von Kobbe, C., Sommers, J.A., Karmakar, P., Opresko, P.L., Piotrowski, J., Dianova, I., Dianov, G.L., Bohr, V.A. EMBO J. (2001) [Pubmed]
  17. FEN1 stimulation of DNA polymerase beta mediates an excision step in mammalian long patch base excision repair. Prasad, R., Dianov, G.L., Bohr, V.A., Wilson, S.H. J. Biol. Chem. (2000) [Pubmed]
  18. Fen1 expression: a novel marker for cell proliferation. Warbrick, E., Coates, P.J., Hall, P.A. J. Pathol. (1998) [Pubmed]
  19. AP endonuclease 1 coordinates flap endonuclease 1 and DNA ligase I activity in long patch base excision repair. Ranalli, T.A., Tom, S., Bambara, R.A. J. Biol. Chem. (2002) [Pubmed]
  20. High mobility of flap endonuclease 1 and DNA polymerase eta associated with replication foci in mammalian S-phase nucleus. Solovjeva, L., Svetlova, M., Sasina, L., Tanaka, K., Saijo, M., Nazarov, I., Bradbury, M., Tomilin, N. Mol. Biol. Cell (2005) [Pubmed]
  21. The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. Lee, B.I., Wilson, D.M. J. Biol. Chem. (1999) [Pubmed]
  22. Defective flap endonuclease 1 activity in mammalian cells is associated with impaired DNA repair and prolonged S phase delay. Shibata, Y., Nakamura, T. J. Biol. Chem. (2002) [Pubmed]
  23. 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. Singh, P., Zheng, L., Chavez, V., Qiu, J., Shen, B. J. Biol. Chem. (2007) [Pubmed]
  24. Multiple but dissectible functions of FEN-1 nucleases in nucleic acid processing, genome stability and diseases. Shen, B., Singh, P., Liu, R., Qiu, J., Zheng, L., Finger, L.D., Alas, S. Bioessays (2005) [Pubmed]
  25. Gene expression of flap endonuclease-1 during cell proliferation and differentiation. Kim, I.S., Lee, M.Y., Lee, I.H., Shin, S.L., Lee, S.Y. Biochim. Biophys. Acta (2000) [Pubmed]
  26. The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Sharma, S., Sommers, J.A., Gary, R.K., Friedrich-Heineken, E., Hübscher, U., Brosh, R.M. Nucleic Acids Res. (2005) [Pubmed]
  27. Mechanisms by which bloom protein can disrupt recombination intermediates of okazaki fragment maturation. Bartos, J.D., Wang, W., Pike, J.E., Bambara, R.A. J. Biol. Chem. (2006) [Pubmed]
  28. p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex. Chen, U., Chen, S., Saha, P., Dutta, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  29. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. Sharma, S., Sommers, J.A., Driscoll, H.C., Uzdilla, L., Wilson, T.M., Brosh, R.M. J. Biol. Chem. (2003) [Pubmed]
  30. Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. Henneke, G., Koundrioukoff, S., Hübscher, U. Oncogene (2003) [Pubmed]
  31. Early immobilization of nuclease FEN1 and accumulation of hRAD18 protein at stalled DNA replication forks in mammalian cells. Nikiforov, A.A., Sasina, L.K., Svetlova, M.P., Solovjeva, L.V., Oei, S.L., Bradbury, E.M., Tomilin, N.V. Dokl. Biochem. Biophys. (2003) [Pubmed]
  32. Preparation and crystallization of human flap endonuclease FEN-1 in complex with proliferating-cell nuclear antigen, PCNA. Sakurai, S., Kitano, K., Okada, K., Hamada, K., Morioka, H., Hakoshima, T. Acta Crystallogr. D Biol. Crystallogr. (2003) [Pubmed]
  33. Flap endonuclease disengages dna2 helicase/nuclease from okazaki fragment flaps. Stewart, J.A., Campbell, J.L., Bambara, R.A. J. Biol. Chem. (2006) [Pubmed]
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