Flap structure-specific endonuclease 1

Flap structure-specific endonuclease 1
PDB rendering based on 1ul1.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1U7B​, 1UL1​, 3Q8K​, 3Q8L​, 3Q8M​, 3UVU​
Identifiers
Symbols	FEN1 ; FEN-1; MF1; RAD2
External IDs	OMIM: 600393 MGI: 102779 HomoloGene: 3034 ChEMBL: 5027 GeneCards: FEN1 Gene
Gene ontology Molecular function • magnesium ion binding • DNA binding • damaged DNA binding • double-stranded DNA binding • endonuclease activity • RNA-DNA hybrid ribonuclease activity • exonuclease activity • protein binding • double-stranded DNA exodeoxyribonuclease activity • 5'-3' exonuclease activity • 5'-flap endonuclease activity • manganese ion binding Cellular component • nucleus • nucleoplasm • nucleolus • mitochondrion • plasma membrane • membrane • protein complex Biological process • mitotic cell cycle • telomere maintenance via recombination • telomere maintenance • DNA replication • DNA strand elongation involved in DNA replication • DNA repair • base-excision repair • double-strand break repair • memory • UV protection • telomere maintenance via semi-conservative replication • DNA replication, removal of RNA primer • nucleic acid phosphodiester bond hydrolysis • RNA phosphodiester bond hydrolysis, endonucleolytic Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2237	14156
Ensembl	ENSG00000168496	ENSMUSG00000024742
UniProt	P39748	P39749
RefSeq (mRNA)	NM_004111	NM_001271614
RefSeq (protein)	NP_004102	NP_001258543
Location (UCSC)	Chr 11: 61.79 – 61.8 Mb	Chr 19: 10.2 – 10.2 Mb
PubMed search

Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.^[1][2]

Function

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.^[2]

Interactions

Flap structure-specific endonuclease 1 has been shown to interact with:

• APEX1,^[3]
• BLM^[4]
• CDK2,^[5]
• CCNA2,^[5]
• EP300,^[6]
• HNRNPA1,^[7]
• PCNA,^{[3][5][6][8][9][10][11]} and
• WRN.^[4][12]

Over expression of FEN1 in cancers

FEN1 is over-expressed in the majority of cancers of the breast,^[13] prostate,^[14] stomach,^[15][16] neuroblastomas,^[17] pancreatic,^[18] and lung.^[19]

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).^[20] MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.^[21] 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).^[22] Various factors determine which pathway will be used for repair of double strand breaks in DNA.^[21] When FEN1 is over-expressed (this occurs when its promoter is hypomethylated^[13]) 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).^[23] Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.^[23] (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.

References

1. 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. PMID 7774922.
2. "Entrez Gene: FEN1 flap structure-specific endonuclease 1".
3. Dianova 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. PMID 11601988.
4. Sharma 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. PMID 14688284.
5. Henneke 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. PMID 12853968.
6. Hasan 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. PMID 11430825.
7. 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. PMID 14690413.
8. Jónsson ZO, Hindges R, Hübscher U (Apr 1998). "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen". EMBO J. 17 (8): 2412–25. doi:10.1093/emboj/17.8.2412. PMC 1170584. PMID 9545252.
9. 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. PMID 9305916.
10. Chen U, Chen S, Saha P, Dutta A (Oct 1996). "p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex". Proc. Natl. Acad. Sci. U.S.A. 93 (21): 11597–602. doi:10.1073/pnas.93.21.11597. PMC 38103. PMID 8876181.
11. 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. PMID 11313979.
12. Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA (Oct 2001). "Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity". EMBO J. 20 (20): 5791–801. doi:10.1093/emboj/20.20.5791. PMC 125684. PMID 11598021.
13. Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008). "Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers". Mol. Cancer Res. 6 (11): 1710–7. doi:10.1158/1541-7786.MCR-08-0269. PMC 2948671. PMID 19010819.
14. 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. PMID 16879693.
15. 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. PMID 15701830.
16. 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. PMID 24590400.
17. 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. PMID 15922863.
18. Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M (2003). "Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays". Am. J. Pathol. 162 (4): 1151–62. doi:10.1016/S0002-9440(10)63911-9. PMC 1851213. PMID 12651607.
19. Nikolova T, Christmann M, Kaina B (2009). "FEN1 is overexpressed in testis, lung and brain tumors". Anticancer Res. 29 (7): 2453–9. PMID 19596913.
20. Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6: e1697. doi:10.1038/cddis.2015.58. PMC 4385936. PMID 25789972.
21. Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA (2005). "Modulation of DNA end joining by nuclear proteins". J. Biol. Chem. 280 (36): 31442–9. doi:10.1074/jbc.M503776200. PMID 16012167.
22. Ottaviani D, LeCain M, Sheer D (2014). "The role of microhomology in genomic structural variation". Trends Genet. 30 (3): 85–94. doi:10.1016/j.tig.2014.01.001. PMID 24503142.
23. Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer

Further reading

• Finger LD, Blanchard MS, Theimer CA, Sengerová B, Singh P, Chavez V, Liu F, Grasby JA, Shen B (2009). "The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis.". J. Biol. Chem. 284 (33): 22184–94. doi:10.1074/jbc.M109.015065. PMC 2755943. PMID 19525235.
• 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. PMID 1477073.
• 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. PMID 7673186.
• 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. PMID 7961795.
• Murray JM, Tavassoli M, al-Harithy R, Sheldrick KS, Lehmann AR, Carr AM, Watts FZ (1994). "Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage.". Mol. Cell. Biol. 14 (7): 4878–88. PMC 358860. PMID 8007985.
• Harrington JJ, Lieber MR (1994). "The characterization of a mammalian DNA structure-specific endonuclease.". EMBO J. 13 (5): 1235–46. PMC 394933. PMID 8131753.
• 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. PMID 8621570.
• Chen U, Chen S, Saha P, Dutta A (1996). "p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex.". Proc. Natl. Acad. Sci. U.S.A. 93 (21): 11597–602. doi:10.1073/pnas.93.21.11597. PMC 38103. PMID 8876181.
• 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. PMID 9178907.
• Klungland A, Lindahl T (1997). "Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1).". EMBO J. 16 (11): 3341–8. doi:10.1093/emboj/16.11.3341. PMC 1169950. PMID 9214649.
• 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. PMID 9305916.
• Stöhr H, Marquardt A, Rivera A, Cooper PR, Nowak NJ, Shows TB, Gerhard DS, Weber BH (1998). "A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1.". Genome Res. 8 (1): 48–56. doi:10.1101/gr.8.1.48. PMC 310689. PMID 9445487.
• Jónsson ZO, Hindges R, Hübscher U (1998). "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen.". EMBO J. 17 (8): 2412–25. doi:10.1093/emboj/17.8.2412. PMC 1170584. PMID 9545252.
• Warbrick E, Heatherington W, Lane DP, Glover DM (1998). "PCNA binding proteins in Drosophila melanogaster : the analysis of a conserved PCNA binding domain.". Nucleic Acids Res. 26 (17): 3925–32. doi:10.1093/nar/26.17.3925. PMC 147798. PMID 9705499.
• 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. PMID 9778254.
• 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. PMID 10460157.
• 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. PMID 10545607.
• 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. PMID 10559261.
• 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. PMID 10635332.
• 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. PMID 11430825.