{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:45:41Z","timestamp":1781109941670,"version":"3.54.1"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"10","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"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":["NS127866"],"award-info":[{"award-number":["NS127866"]}],"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":["NS049206"],"award-info":[{"award-number":["NS049206"]}],"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":["NS114065"],"award-info":[{"award-number":["NS114065"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM149546"],"award-info":[{"award-number":["R35GM149546"]}],"id":[{"id":"10.13039\/100000057","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":["NS091161"],"award-info":[{"award-number":["NS091161"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["CHDI JSC"],"award-info":[{"award-number":["CHDI JSC"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023581","name":"NSF | NSF Graduate Research Fellowship Program","doi-asserted-by":"publisher","award":["DGE-1841052"],"award-info":[{"award-number":["DGE-1841052"]}],"id":[{"id":"10.13039\/100023581","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":[[2026,3,10]]},"abstract":"<jats:p>\n                    Huntington\u2019s disease (HD) is a fatal neurodegenerative disorder caused by inheriting an expanded CAG repeat tract in the huntingtin gene (\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    ) that further expands in somatic cells over an individual\u2019s lifetime. Genome-wide association studies have provided critical insight into factors that modify the course of disease. These include DNA repair genes that alter the rate of somatic expansion and other genes that do not appear to directly influence this process. One modifier gene is DNA ligase 1 (\n                    <jats:italic toggle=\"yes\">LIG1<\/jats:italic>\n                    ), in which a variant specifying a lysine to asparagine substitution (K845N) is associated with a profound (7 to 8 y) delay in the onset of motor signs. Here, we have taken a multifaceted approach to gain insight into the protective nature of this variant in HD. We demonstrate using in vitro ligase assays and enzyme kinetics that K845N enhances discrimination toward mismatched substrates and increases repair fidelity. Consistent with increased ligation fidelity, K845N confers protection against oxidative stress in cell-based assays. Finally, we demonstrate that the mouse LIG1 K843N orthologue suppresses somatic CAG expansion in HD knock-in mice. Overall, our data provide evidence that altered LIG1 function due to the K845N substitution may contribute to HD clinical delay by slowing somatic expansion in the brain and protecting the genome globally against damage. Significantly, our results provide a mechanistic foundation for considering DNA ligase fidelity as a therapeutic target in HD and potentially in other trinucleotide repeat disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2518854123","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T20:10:06Z","timestamp":1772482206000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Huntington\u2019s disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-1677","authenticated-orcid":false,"given":"Eunhye","family":"Lee","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-8470","authenticated-orcid":false,"given":"Wonju","family":"Kim","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Beier","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of Michigan Medical School","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejin","family":"Lee","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kovalenko","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faaiza","family":"Saif","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7003-4347","authenticated-orcid":false,"given":"Esaria","family":"Oliver","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhairavi","family":"Srinageshwar","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Murtha","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa A.","family":"Andrew","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Jiang","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Gillis","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Demelo","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayla","family":"Ruliera","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Lucente","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung","family":"Kwak","sequence":"additional","affiliation":[{"name":"CHDI Management Inc.","place":["Princeton"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramee","family":"Lee","sequence":"additional","affiliation":[{"name":"CHDI Management Inc.","place":["Princeton"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6744-2805","authenticated-orcid":false,"given":"Ricardo Mouro","family":"Pinto","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcy E.","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F.","family":"Gusella","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]},{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7853-8626","authenticated-orcid":false,"given":"Patrick J.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of Michigan Medical School","place":["Ann Arbor"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa C.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard","place":["Cambridge"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4246-3356","authenticated-orcid":false,"given":"Ihn Sik","family":"Seong","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital","place":["Boston"]},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"957","article-title":"Huntington\u2019s disease: A clinical, genetic and molecular model for polyglutamine repeat disorders","volume":"354","author":"Harper P. S.","year":"1999","unstructured":"P. S. Harper, Huntington\u2019s disease: A clinical, genetic and molecular model for polyglutamine repeat disorders. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 957\u2013961 (1999).","journal-title":"Philos. Trans. R. Soc. Lond. B. Biol. Sci."},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp242"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg352"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa139"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01653-6"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.12.009"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.11.038"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0893-387"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318249f683"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0893-398"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.003"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.036"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30161-8"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200427"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.03.004"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02191-5"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02054-5"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0896-489"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.7.1551"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.77.061306.123941"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gez026"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.186.4166.790"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03082"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13478-7"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99629"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90450-Q"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)91266-B"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107957"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1297"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh909"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki518"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","DOI":"10.21769\/BioProtoc.2341","article-title":"In vitro assay to measure DNA polymerase \u03b2 nucleotide insertion coupled with the DNA ligation reaction during base excision repair","volume":"7","author":"\u00c7a\u011flayan M.","year":"2017","unstructured":"M. \u00c7a\u011flayan, S. H. Wilson, In vitro assay to measure DNA polymerase \u03b2 nucleotide insertion coupled with the DNA ligation reaction during base excision repair. Bio. Protoc. 7, e2341 (2017).","journal-title":"Bio. Protoc."},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.248831"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom15040527"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.2.400"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023647"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.09.014"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044273"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003930"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab152"},{"key":"e_1_3_4_43_2","first-page":"4065","article-title":"Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene","volume":"62","author":"Harrison C.","year":"2002","unstructured":"C. Harrison, A. M. Ketchen, N. J. Redhead, M. J. O\u2019Sullivan, D. W. Melton, Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene. Cancer Res. 62, 4065\u20134074 (2002).","journal-title":"Cancer Res."},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05164"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-184"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001-189"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703774200"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35475-z"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr099"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.034405"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2302103120"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909087107"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.027"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05778"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12465"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcpr.1993.1034"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.134"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07901-8"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.116.195578"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55911"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-4-29"},{"key":"e_1_3_4_63_2","unstructured":"E. Lee Duplex sequencing of mutation frequency in HEK293 cells expressing LIG1 WT and K845N. NCBI Sequence Read Archive (SRA). https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1425166. Deposited 18 February 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2518854123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T20:11:04Z","timestamp":1772914264000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2518854123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":63,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,3,10]]}},"alternative-id":["10.1073\/pnas.2518854123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2518854123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]},"assertion":[{"value":"2025-07-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2518854123"}}