{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:09:51Z","timestamp":1792076991484,"version":"4.4.0"},"reference-count":80,"publisher":"National Academy of Sciences","issue":"13","license":[{"start":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T00:00:00Z","timestamp":1710720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RR160101"],"award-info":[{"award-number":["RR160101"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001671","name":"Hereditary Disease Foundation","doi-asserted-by":"publisher","award":["GAA202008"],"award-info":[{"award-number":["GAA202008"]}],"id":[{"id":"10.13039\/100001671","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":[[2024,3,26]]},"abstract":"<jats:p>\n                    Huntington\u2019s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (\n                    <jats:italic>HTT<\/jats:italic>\n                    ) gene. The repeat-expanded\n                    <jats:italic>HTT<\/jats:italic>\n                    encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS\u2013STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutL\u03b1 (MLH1\u2013PMS2), a negative regulator of Exo1. While the HTT\u2013Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT\u2013MutL\u03b1 interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutL\u03b1, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS\u2013STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS\u2013STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2313652121","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T15:03:07Z","timestamp":1710774187000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS\u2013STING-dependent apoptosis"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-0006","authenticated-orcid":false,"given":"Xiao","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"},{"name":"The Ministry of Education Key Laboratory of Reproductive Genetics, Department of Reproductive Endocrinology, Women\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-6533","authenticated-orcid":false,"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-4819","authenticated-orcid":false,"given":"Chao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhen","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-8460","authenticated-orcid":false,"given":"Junqiu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-0610","authenticated-orcid":false,"given":"Junhong","family":"Guan","sequence":"additional","affiliation":[{"name":"Cui-ying Experimental Center, Lanzhou University Second Hospital, Lanzhou 730030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &amp; Human behavior, University of California, Los Angeles, CA 90095"},{"name":"Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. Willian","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience &amp; Human behavior, University of California, Los Angeles, CA 90095"},{"name":"Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9842-4578","authenticated-orcid":false,"given":"Guo-Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390"},{"name":"Institute for Cancer Research, Chinese Institutes for Medical Research, Beijing 100069, China"},{"name":"School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80514-0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221891110"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1806"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-10-03705.2000"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81782-1"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.03.010"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq313"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/77528"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2005.09.011"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080178"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr0700753"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/currents.RRN1231"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2002144117"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI150328"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat8657"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23449"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180139"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.102"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00848.2018"},{"key":"e_1_3_4_20_2","first-page":"395","article-title":"Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex","volume":"26","author":"Maiuri T.","year":"2017","unstructured":"T. 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