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Flap structure-specific endonuclease 1
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<h2 id="function">Function</h2> <p>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 <a href="/facts/Okazaki_fragment/TXkaVB27">Okazaki fragments</a> in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch <a href="/facts/Base_excision_repair/QQIlyTxY">base excision repair</a> 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 <a href="/facts/Trinucleotide_repeat/6GEwqSS2">trinucleotide repeats</a> 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.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>Flap structure-specific endonuclease 1 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/APEX1/gAX0aGWf">APEX1</a>,<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a></li> <li><a href="/facts/Bloom_syndrome_protein/0fbyX53T">BLM</a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li> <li><a href="/facts/Cyclin-dependent_kinase_2/ga3e7mvK">CDK2</a>,<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a></li> <li><a href="/facts/Cyclin_A2/aNXYTyrY">CCNA2</a>,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a></li> <li><a href="/facts/EP300/7WU3jvjy">EP300</a>,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li> <li><a href="/facts/Heterogeneous_nuclear_ribonucleoprotein_A1/h0rJkpwj">HNRNPA1</a>,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a></li> <li><a href="/facts/PCNA/KIBbmpXz">PCNA</a>,<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> and</li> <li><a href="/facts/Werner_syndrome_ATP-dependent_helicase/t2n8XVwF">WRN</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a></li></ul> <h2 id="over-expression-of-fen1-in-cancers">Over expression of FEN1 in cancers</h2> <p>FEN1 is over-expressed in the majority of cancers of the breast,<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> prostate,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> stomach,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> neuroblastomas,<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> pancreatic,<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> and lung.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> </p><p>FEN1 is an essential enzyme in an inaccurate pathway for repair of double-strand breaks in DNA called microhomology-dependent alternative end joining or <a href="/facts/Microhomology-mediated_end_joining/9HqLXPvm">microhomology-mediated end joining</a> (MMEJ).<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Several other pathways can also repair double-strand breaks in DNA, including the less inaccurate pathway of <a href="/facts/Non-homologous_end_joining/xvHqwBPt">non-homologous end joining</a> (NHEJ) and accurate pathways using <a href="/facts/Homologous_recombination/WU0IIVVv">homologous recombinational</a> repair (HRR).<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> Various factors determine which pathway will be used for repair of double strand breaks in DNA.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> When FEN1 is over-expressed (this occurs when its promoter is hypomethylated<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a>) the highly inaccurate MMEJ pathway may be favored, causing a higher rate of mutation and increased risk of cancer. </p><p>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 <a href="/facts/Cancer_syndrome/tQBAWxaR">cancer syndromes</a>). Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also <a href="/facts/DNA_repair/hsURuYYq">Epigenetically reduced DNA repair and cancer</a>.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (<a href="/facts/DNA_repair/hsURuYYq">translesion synthesis</a>), 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. </p> <h2 id="therapeutic-target-for-human-cancer">Therapeutic target for human cancer</h2> <p>Therapeutic targets for cancers with <a href="/facts/BRCA1/xHDwxARA">BRCA1</a> or <a href="/facts/BRCA2/eDUI83G1">BRCA2</a> defects were identified by analysis of <a href="/facts/Synthetic_lethality/zR70fz4G">synthetic lethal relationships</a> using <i><a href="/facts/Saccharomyces_cerevisiae/sX9MGFrz">Saccharomyces cerevisiae</a></i>, human cell lines and mice as model systems.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> 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 <a href="/facts/Breast_cancer/6hME580v">breast cancer</a> and <a href="/facts/Ovarian_cancer/fsWbh3Tn">ovarian cancer</a>. Such cancers are deficient in the <a href="/facts/DNA_repair/hsURuYYq">DNA repair</a> process of <a href="/facts/Homologous_recombination/WU0IIVVv">homologous recombination</a> (HR). FEN1 protein is essential for the alternate DNA repair pathway, <a href="/facts/Microhomology-mediated_end_joining/9HqLXPvm">microhomology-mediated end joining</a> (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 <a href="/facts/Synthetic_lethality/zR70fz4G">synthetic lethality</a>. </p> <h2 id="further-reading">Further reading</h2> <ul><li>Finger LD, Blanchard MS, Theimer CA, Sengerová B, Singh P, Chavez V, et al. (August 2009). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755943">"The 3'-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis"</a>. <i>The Journal of Biological Chemistry</i>. 284 (33): 22184–22194. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.M109.015065">10.1074/jbc.M109.015065</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755943">2755943</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/19525235">19525235</a>.</li> <li>Kemeny MM, Alava G, Oliver JM (November 1992). "Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2". <i>Journal of Immunotherapy</i>. 12 (4): 219–223. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1097%2F00002371-199211000-00001">10.1097/00002371-199211000-00001</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/1477073">1477073</a>.</li> <li>Li X, Li J, Harrington J, Lieber MR, Burgers PM (September 1995). <a href="https://doi.org/10.1074%2Fjbc.270.38.22109">"Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen"</a>. <i>The Journal of Biological Chemistry</i>. 270 (38): 22109–22112. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.270.38.22109">10.1074/jbc.270.38.22109</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7673186">7673186</a>.</li> <li>Robins P, Pappin DJ, Wood RD, Lindahl T (November 1994). <a href="https://doi.org/10.1016%2FS0021-9258%2819%2961935-6">"Structural and functional homology between mammalian DNase IV and the 5'-nuclease domain of Escherichia coli DNA polymerase I"</a>. <i>The Journal of Biological Chemistry</i>. 269 (46): 28535–28538. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0021-9258%2819%2961935-6">10.1016/S0021-9258(19)61935-6</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/7961795">7961795</a>.</li> <li>Murray JM, Tavassoli M, al-Harithy R, Sheldrick KS, Lehmann AR, Carr AM, Watts FZ (July 1994). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC358860">"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"</a>. <i>Molecular and Cellular Biology</i>. 14 (7): 4878–4888. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2FMCB.14.7.4878">10.1128/MCB.14.7.4878</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC358860">358860</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8007985">8007985</a>.</li> <li>Harrington JJ, Lieber MR (March 1994). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC394933">"The characterization of a mammalian DNA structure-specific endonuclease"</a>. <i>The EMBO Journal</i>. 13 (5): 1235–1246. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fj.1460-2075.1994.tb06373.x">10.1002/j.1460-2075.1994.tb06373.x</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC394933">394933</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8131753">8131753</a>.</li> <li>Shen B, Nolan JP, Sklar LA, Park MS (April 1996). <a href="https://doi.org/10.1074%2Fjbc.271.16.9173">"Essential amino acids for substrate binding and catalysis of human flap endonuclease 1"</a>. <i>The Journal of Biological Chemistry</i>. 271 (16): 9173–9176. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.271.16.9173">10.1074/jbc.271.16.9173</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8621570">8621570</a>.</li> <li>Chen U, Chen S, Saha P, Dutta A (October 1996). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC38103">"p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 93 (21): 11597–11602. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1996PNAS...9311597C">1996PNAS...9311597C</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.93.21.11597">10.1073/pnas.93.21.11597</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC38103">38103</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8876181">8876181</a>.</li> <li>Warbrick E, Lane DP, Glover DM, Cox LS (May 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". <i>Oncogene</i>. 14 (19): 2313–2321. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fsj.onc.1201072">10.1038/sj.onc.1201072</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9178907">9178907</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:29525059">29525059</a>.</li> <li>Klungland A, Lindahl T (June 1997). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1169950">"Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1)"</a>. <i>The EMBO Journal</i>. 16 (11): 3341–3348. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Femboj%2F16.11.3341">10.1093/emboj/16.11.3341</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1169950">1169950</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9214649">9214649</a>.</li> <li>Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (September 1997). <a href="https://doi.org/10.1074%2Fjbc.272.39.24522">"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"</a>. <i>The Journal of Biological Chemistry</i>. 272 (39): 24522–24529. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.272.39.24522">10.1074/jbc.272.39.24522</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9305916">9305916</a>.</li> <li>Stöhr H, Marquardt A, Rivera A, Cooper PR, Nowak NJ, Shows TB, et al. 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"Replication protein A stimulates proliferating cell nuclear antigen-dependent repair of abasic sites in DNA by human cell extracts". <i>Biochemistry</i>. 38 (34): 11021–11025. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1021%2Fbi9908890">10.1021/bi9908890</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10460157">10460157</a>.</li> <li>Greene AL, Snipe JR, Gordenin DA, Resnick MA (November 1999). <a href="https://zenodo.org/records/1234333/files/article.pdf">"Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability"</a> (PDF). <i>Human Molecular Genetics</i>. 8 (12): 2263–2273. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fhmg%2F8.12.2263">10.1093/hmg/8.12.2263</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10545607">10545607</a>.</li> <li>Matsumoto Y, Kim K, Hurwitz J, Gary R, Levin DS, Tomkinson AE, Park MS (November 1999). <a href="https://doi.org/10.1074%2Fjbc.274.47.33703">"Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteins"</a>. <i>The Journal of Biological Chemistry</i>. 274 (47): 33703–33708. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.274.47.33703">10.1074/jbc.274.47.33703</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10559261">10559261</a>.</li> <li>Spiro C, Pelletier R, Rolfsmeier ML, Dixon MJ, Lahue RS, Gupta G, et al. 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