Flap structure-specific endonuclease 1

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Flap structure-specific endonuclease 1
Protein FEN1 PDB 1ul1.png
PDB rendering based on 1ul1.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols FEN1 ; FEN-1; MF1; RAD2
External IDs OMIM600393 MGI102779 HomoloGene3034 ChEMBL: 5027 GeneCards: FEN1 Gene
RNA expression pattern
PBB GE FEN1 204767 s at tn.png
PBB GE FEN1 204768 s at tn.png
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:
61.56 – 61.56 Mb
Chr 19:
10.2 – 10.2 Mb
PubMed search [1] [2]

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

Function[edit]

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[edit]

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

Over expression of FEN1 in cancers[edit]

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[edit]

  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. ^ a b "Entrez Gene: FEN1 flap structure-specific endonuclease 1". 
  3. ^ a b 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. ^ a b 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. ^ a b c 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. ^ a b Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P et al. (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 et al. (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 et al. (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. ^ a b Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W et al. (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 et al. (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 et al. (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 et al. (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 et al. (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. ^ Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C et al. (2003). "Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer". Oncogene 22 (46): 7243–6. doi:10.1038/sj.onc.1206977. PMID 14562054. 
  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. PMID 25789972. 
  21. ^ a b 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. ^ a b 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[edit]