The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases are prevented from binding to their complementary base pair—despite any base pairing downstream) in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions.
FEN1 is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreatic, and lung.
FEN1 is an essential enzyme in an inaccurate pathway for repair of double-strand breaks in DNA called microhomology-dependent alternative end joining or microhomology-mediated end joining (MMEJ). MMEJ always involves at least a small deletion, so that it is a mutagenic pathway. Several other pathways can also repair double-strand breaks in DNA, including the less inaccurate pathway of non-homologous end joining (NHEJ) and accurate pathways using homologous recombinational repair (HRR). Various factors determine which pathway will be used for repair of double strand breaks in DNA. When FEN1 is over-expressed (this occurs when its promoter is hypomethylated) the highly inaccurate MMEJ pathway may be favored, causing a higher rate of mutation and increased risk of cancer.
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is unusual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes). Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, FEN1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, leads to cancer.
^Hiraoka LR, Harrington JJ, Gerhard DS, Lieber MR, Hsieh CL (Jul 1995). "Sequence of human FEN-1, a structure-specific endonuclease, and chromosomal localization of the gene (FEN1) in mouse and human". Genomics. 25 (1): 220–5. doi:10.1016/0888-7543(95)80129-A. PMID7774922.
^ abDianova II, Bohr VA, Dianov GL (Oct 2001). "Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair". Biochemistry. 40 (42): 12639–44. doi:10.1021/bi011117i. PMID11601988.
^ abSharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (Mar 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56. doi:10.1074/jbc.M309898200. PMID14688284.
^ abcHenneke G, Koundrioukoff S, Hübscher U (Jul 2003). "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene. 22 (28): 4301–13. doi:10.1038/sj.onc.1206606. PMID12853968.
^ abHasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO (Jun 2001). "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300". Mol. Cell. 7 (6): 1221–31. doi:10.1016/s1097-2765(01)00272-6. PMID11430825.
^Chai Q, Zheng L, Zhou M, Turchi JJ, Shen B (Dec 2003). "Interaction and stimulation of human FEN-1 nuclease activities by heterogeneous nuclear ribonucleoprotein A1 in alpha-segment processing during Okazaki fragment maturation". Biochemistry. 42 (51): 15045–52. doi:10.1021/bi035364t. PMID14690413.
^Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (Sep 1997). "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. 272 (39): 24522–9. doi:10.1074/jbc.272.39.24522. PMID9305916.
^Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y (Jan 2001). "p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues". Oncogene. 20 (4): 484–9. doi:10.1038/sj.onc.1204113. PMID11313979.
^Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS (2006). "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". BJU Int. 98 (2): 445–51. doi:10.1111/j.1464-410X.2006.06224.x. PMID16879693.
^Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS (2005). "Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells". Clin. Cancer Res. 11 (2 Pt 1): 473–82. PMID15701830.
^Wang K, Xie C, Chen D (2014). "Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis". Int. J. Mol. Med. 33 (5): 1268–74. doi:10.3892/ijmm.2014.1682. PMID24590400.
^Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A (2005). "Genome-wide analysis of gene expression in neuroblastomas detected by mass screening". Cancer Lett. 225 (1): 111–20. doi:10.1016/j.canlet.2004.10.035. PMID15922863.
Kemeny MM, Alava G, Oliver JM (1993). "Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2.". J. Immunother. 12 (4): 219–23. doi:10.1097/00002371-199211000-00001. PMID1477073.
Li X, Li J, Harrington J, Lieber MR, Burgers PM (1995). "Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen.". J. Biol. Chem. 270 (38): 22109–12. doi:10.1074/jbc.270.38.22109. PMID7673186.
Robins P, Pappin DJ, Wood RD, Lindahl T (1994). "Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I.". J. Biol. Chem. 269 (46): 28535–8. PMID7961795.
Shen B, Nolan JP, Sklar LA, Park MS (1996). "Essential amino acids for substrate binding and catalysis of human flap endonuclease 1.". J. Biol. Chem. 271 (16): 9173–6. doi:10.1074/jbc.271.16.9173. PMID8621570.
Warbrick E, Lane DP, Glover DM, Cox LS (1997). "Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair.". Oncogene. 14 (19): 2313–21. doi:10.1038/sj.onc.1201072. PMID9178907.
Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (1997). "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. 272 (39): 24522–9. doi:10.1074/jbc.272.39.24522. PMID9305916.
Hosfield DJ, Mol CD, Shen B, Tainer JA (1998). "Structure of the DNA repair and replication endonuclease and exonuclease FEN-1: coupling DNA and PCNA binding to FEN-1 activity.". Cell. 95 (1): 135–46. doi:10.1016/S0092-8674(00)81789-4. PMID9778254.
Dianov GL, Jensen BR, Kenny MK, Bohr VA (1999). "Replication protein A stimulates proliferating cell nuclear antigen-dependent repair of abasic sites in DNA by human cell extracts.". Biochemistry. 38 (34): 11021–5. doi:10.1021/bi9908890. PMID10460157.
Greene AL, Snipe JR, Gordenin DA, Resnick MA (1999). "Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability.". Hum. Mol. Genet. 8 (12): 2263–73. doi:10.1093/hmg/8.12.2263. PMID10545607.
Matsumoto Y, Kim K, Hurwitz J, Gary R, Levin DS, Tomkinson AE, Park MS (1999). "Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteins.". J. Biol. Chem. 274 (47): 33703–8. doi:10.1074/jbc.274.47.33703. PMID10559261.
Spiro C, Pelletier R, Rolfsmeier ML, Dixon MJ, Lahue RS, Gupta G, Park MS, Chen X, Mariappan SV, McMurray CT (2000). "Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats.". Mol. Cell. 4 (6): 1079–85. doi:10.1016/S1097-2765(00)80236-1. PMID10635332.
Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO (2001). "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300.". Mol. Cell. 7 (6): 1221–31. doi:10.1016/S1097-2765(01)00272-6. PMID11430825.