{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T23:57:41Z","timestamp":1783814261179,"version":"3.55.0"},"reference-count":72,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T00:00:00Z","timestamp":1691366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS118082"],"award-info":[{"award-number":["R01 NS118082"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R03 NS114976"],"award-info":[{"award-number":["R03 NS114976"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:p>\n                    Human genome-wide association studies have identified\n                    <jats:italic>FAN1<\/jats:italic>\n                    and several DNA mismatch repair (MMR) genes as modifiers of Huntington\u2019s disease age of onset. In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. Here, we describe a strand-directed, extrusion-provoked nuclease function of FAN1 that is activated by RFC, PCNA, and ATP at physiological ionic strength. Activation of FAN1 in this manner results in DNA cleavage in the vicinity of triplet repeat extrahelical extrusions thereby leading to their removal in human cell extracts. The role of PCNA and RFC is to confer strand directionality to the FAN1 nuclease, and this reaction requires a physical interaction between PCNA and FAN1. Using cell extracts, we show that FAN1-dependent CAG extrusion removal relies on a very short patch excision-repair mechanism that competes with MutS\u03b2-dependent MMR which is characterized by longer excision tracts. These results provide a mechanistic basis for the role of FAN1 in preventing repeat expansion and could explain the antagonistic effects of MMR and FAN1 in disease onset\/progression.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2302103120","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T15:11:27Z","timestamp":1691421087000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":35,"title":["FAN1 removes triplet repeat extrusions via a PCNA- and RFC-dependent mechanism"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6699-6769","authenticated-orcid":false,"given":"Ashutosh S.","family":"Phadte","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuri","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hope","family":"Ebert","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haaris","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3189-2262","authenticated-orcid":false,"given":"Essam Abed","family":"Elrazaq","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6799-4626","authenticated-orcid":false,"given":"Konstantin E.","family":"Komolov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4868-6024","authenticated-orcid":false,"given":"Anna","family":"Pluciennik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,8,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-072610-155046"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(20)30343-4"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2007.04.003"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV119.007678"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.11.008"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr0404794"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-112414-054722"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060614-034010"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200438"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.003"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30161-8"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx286"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24656"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz115"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy375"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.036"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.06.023"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.05.012"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","unstructured":"J. M. Loupe Promotion of somatic CAG repeat expansion by Fan1 knock-out in Huntington\u2019s disease knock-in mice is blocked by Mlh1 knock-out. Hum. Mol. Genet. 29 3044\u20133053 (2020) 10.1093\/hmg\/ddaa196.","DOI":"10.1093\/hmg\/ddaa196"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2018.07.001"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.022"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1011081107"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.021"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192656"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110078"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1401940114"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.05.039"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311325110"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010662107"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.38.22109"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1702561114"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01074-6"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6603(04)78006-X"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.1996.07007.x"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)80673-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109684200"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.104125"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81347-1"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10040570"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C109.014977"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609989200"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109649"},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","unstructured":"A. Porro FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG\/CTG repeats. Sci. Adv. 7 eabf7906 (2021). eabf7906","DOI":"10.1126\/sciadv.abf7906"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00303-21"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4958"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001140200"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7973637"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1638"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50276-9"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvv043"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.06.001"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2347"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-420604"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.276261.115"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.276287.115"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11863"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab899"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6726"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.2.1421"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02585"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.045"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.09.014"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa139"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01033-5"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318971110"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-021-00468-y"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914718117"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008902"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007719"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003930"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab152"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.2.191"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2302103120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:43:52Z","timestamp":1695289432000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2302103120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,7]]},"references-count":72,"journal-issue":{"issue":"33","published-print":{"date-parts":[[2023,8,15]]}},"alternative-id":["10.1073\/pnas.2302103120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2302103120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,7]]},"assertion":[{"value":"2023-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2302103120"}}