Flap structure-specific endonuclease 1

{{Short description|Protein-coding gene in the species Homo sapiens}}

Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.{{cite journal | vauthors = Hiraoka LR, Harrington JJ, Gerhard DS, Lieber MR, Hsieh CL | title = Sequence of human FEN-1, a structure-specific endonuclease, and chromosomal localization of the gene (FEN1) in mouse and human | journal = Genomics | volume = 25 | issue = 1 | pages = 220–225 | date = January 1995 | pmid = 7774922 | doi = 10.1016/0888-7543(95)80129-A }}{{cite web | title = Entrez Gene: FEN1 flap structure-specific endonuclease 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2237}}

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.

Interactions

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

APEX1,
BLM
CDK2,{{cite journal | vauthors = Henneke G, Koundrioukoff S, Hübscher U | title = Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation | journal = Oncogene | volume = 22 | issue = 28 | pages = 4301–4313 | date = July 2003 | pmid = 12853968 | doi = 10.1038/sj.onc.1206606 | s2cid = 5787920 | doi-access = }}
CCNA2,
EP300,{{cite journal | vauthors = Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO | display-authors = 6 | title = Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300 | journal = Molecular Cell | volume = 7 | issue = 6 | pages = 1221–1231 | date = June 2001 | pmid = 11430825 | doi = 10.1016/s1097-2765(01)00272-6 | doi-access = free }}
HNRNPA1,{{cite journal | vauthors = Chai Q, Zheng L, Zhou M, Turchi JJ, Shen B | title = Interaction and stimulation of human FEN-1 nuclease activities by heterogeneous nuclear ribonucleoprotein A1 in alpha-segment processing during Okazaki fragment maturation | journal = Biochemistry | volume = 42 | issue = 51 | pages = 15045–15052 | date = December 2003 | pmid = 14690413 | doi = 10.1021/bi035364t }}
PCNA,{{cite journal | vauthors = Dianova II, Bohr VA, Dianov GL | title = Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair | journal = Biochemistry | volume = 40 | issue = 42 | pages = 12639–12644 | date = October 2001 | pmid = 11601988 | doi = 10.1021/bi011117i }}{{cite journal | vauthors = Jónsson ZO, Hindges R, Hübscher U | title = Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen | journal = The EMBO Journal | volume = 17 | issue = 8 | pages = 2412–2425 | date = April 1998 | pmid = 9545252 | pmc = 1170584 | doi = 10.1093/emboj/17.8.2412 }}{{cite journal | vauthors = Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS | title = 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 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 39 | pages = 24522–24529 | date = September 1997 | pmid = 9305916 | doi = 10.1074/jbc.272.39.24522 | doi-access = free }}{{cite journal | vauthors = Chen U, Chen S, Saha P, Dutta A | title = p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 21 | pages = 11597–11602 | date = October 1996 | pmid = 8876181 | pmc = 38103 | doi = 10.1073/pnas.93.21.11597 | doi-access = free | bibcode = 1996PNAS...9311597C }}{{cite journal | vauthors = Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y | display-authors = 6 | title = p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues | journal = Oncogene | volume = 20 | issue = 4 | pages = 484–489 | date = January 2001 | pmid = 11313979 | doi = 10.1038/sj.onc.1204113 | s2cid = 39144360 | doi-access = }} and
WRN.{{cite journal | vauthors = Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM | title = Stimulation of flap endonuclease-1 by the Bloom's syndrome protein | journal = The Journal of Biological Chemistry | volume = 279 | issue = 11 | pages = 9847–9856 | date = March 2004 | pmid = 14688284 | doi = 10.1074/jbc.M309898200 | doi-access = free }}{{cite journal | vauthors = Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA | display-authors = 6 | title = Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity | journal = The EMBO Journal | volume = 20 | issue = 20 | pages = 5791–5801 | date = October 2001 | pmid = 11598021 | pmc = 125684 | doi = 10.1093/emboj/20.20.5791 }}

Over expression of FEN1 in cancers

FEN1 is over-expressed in the majority of cancers of the breast,{{cite journal | vauthors = Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B | display-authors = 6 | title = Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers | journal = Molecular Cancer Research | volume = 6 | issue = 11 | pages = 1710–1717 | date = November 2008 | pmid = 19010819 | pmc = 2948671 | doi = 10.1158/1541-7786.MCR-08-0269 }} prostate,{{cite journal | vauthors = Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS | display-authors = 6 | title = Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score | journal = BJU International | volume = 98 | issue = 2 | pages = 445–451 | date = August 2006 | pmid = 16879693 | doi = 10.1111/j.1464-410X.2006.06224.x | s2cid = 22165252 }} stomach,{{cite journal | vauthors = Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Kim YS, Kim JG, Kim NS | display-authors = 6 | title = Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells | journal = Clinical Cancer Research | volume = 11 | issue = 2 Pt 1 | pages = 473–482 | date = January 2005 | pmid = 15701830 | doi = 10.1158/1078-0432.473.11.2 | doi-access = free }}{{cite journal | vauthors = Wang K, Xie C, Chen D | title = Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis | journal = International Journal of Molecular Medicine | volume = 33 | issue = 5 | pages = 1268–1274 | date = May 2014 | pmid = 24590400 | doi = 10.3892/ijmm.2014.1682 | doi-access = free }} neuroblastomas,{{cite journal | vauthors = Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A | display-authors = 6 | title = Genome-wide analysis of gene expression in neuroblastomas detected by mass screening | journal = Cancer Letters | volume = 225 | issue = 1 | pages = 111–120 | date = July 2005 | pmid = 15922863 | doi = 10.1016/j.canlet.2004.10.035 | s2cid = 44644467 | url = https://hal.archives-ouvertes.fr/hal-00157917/file/Cancer_Letters_2004.pdf }} pancreatic,{{cite journal | vauthors = 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 | display-authors = 6 | title = Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays | journal = The American Journal of Pathology | volume = 162 | issue = 4 | pages = 1151–1162 | date = April 2003 | pmid = 12651607 | pmc = 1851213 | doi = 10.1016/S0002-9440(10)63911-9 }} and lung.{{cite journal | vauthors = Nikolova T, Christmann M, Kaina B | title = FEN1 is overexpressed in testis, lung and brain tumors | journal = Anticancer Research | volume = 29 | issue = 7 | pages = 2453–2459 | date = July 2009 | pmid = 19596913 }}

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).{{cite journal | vauthors = Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC | title = Homology and enzymatic requirements of microhomology-dependent alternative end joining | journal = Cell Death & Disease | volume = 6 | issue = 3 | pages = e1697 | date = March 2015 | pmid = 25789972 | pmc = 4385936 | doi = 10.1038/cddis.2015.58 }} MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.{{cite journal | vauthors = Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA | title = Modulation of DNA end joining by nuclear proteins | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31442–31449 | date = September 2005 | pmid = 16012167 | doi = 10.1074/jbc.M503776200 | doi-access = free }} 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).{{cite journal | vauthors = Ottaviani D, LeCain M, Sheer D | title = The role of microhomology in genomic structural variation | journal = Trends in Genetics | volume = 30 | issue = 3 | pages = 85–94 | date = March 2014 | pmid = 24503142 | doi = 10.1016/j.tig.2014.01.001 | doi-access = free }} 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).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} (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.

Therapeutic target for human cancer

Therapeutic targets for cancers with BRCA1 or BRCA2 defects were identified by analysis of synthetic lethal relationships using Saccharomyces cerevisiae, human cell lines and mice as model systems.{{cite journal | vauthors = Guo E, Ishii Y, Mueller J, Srivatsan A, Gahman T, Putnam CD, Wang JY, Kolodner RD | display-authors = 6 | title = FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 32 | pages = 19415–19424 | date = August 2020 | pmid = 32719125 | pmc = 7431096 | doi = 10.1073/pnas.2009237117 | bibcode = 2020PNAS..11719415G | doi-access = free }} Inhibition of the FEN1 repair protein with small molecule inhibitors was observed to preferentially kill cancer cell lines that were already deficient in expression of BRCA1 and BRCA2 proteins. Cancers that often have defective expression of BRCA1 or BRCA2 include breast cancer and ovarian cancer. Such cancers are deficient in the DNA repair process of homologous recombination (HR). FEN1 protein is essential for the alternate DNA repair pathway, microhomology-mediated end joining (MMEJ). Thus, FEN1 inhibition of the MMEJ repair pathway of cancer cells, that are already defective in the HR repair pathway, causes a second repair pathway to be deficient leading to synthetic lethality.

Flap structure-specific endonuclease 1

Function

Interactions

Over expression of FEN1 in cancers

Therapeutic target for human cancer

References

Further reading