{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:58:50Z","timestamp":1773903530966,"version":"3.50.1"},"posted":{"date-parts":[[2024,9,20]]},"group-title":"Neuroscience","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T00:00:00Z","timestamp":1726790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,20]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Persistent DNA double-strand breaks (DSBs) are enigmatically implicated in neurodegenerative diseases including Huntington\u2019s disease (HD), the inherited late-onset disorder caused by CAG repeat elongations in Huntingtin (HTT). Here we combine biochemistry, computation and molecular cell biology to unveil a mechanism whereby HTT coordinates a Transcription-Coupled Non-Homologous End-Joining (TC-NHEJ) complex. HTT joins TC-NHEJ proteins PNKP, Ku70\/80, and XRCC4 with chromatin remodeler Brahma-related Gene 1 (BRG1) to resolve transcription-associated DSBs in brain. HTT recruitment to DSBs in transcriptionally active gene- rich regions is BRG1-dependent while efficient TC-NHEJ protein recruitment is HTT-dependent. Notably, mHTT compromises TC-NHEJ interactions and repair activity, promoting DSB accumulation in HD tissues. Importantly, HTT or PNKP overexpression restores TC-NHEJ in a\n                  <jats:italic>Drosophila<\/jats:italic>\n                  HD model dramatically improving genome integrity, motor defects, and lifespan. Collective results uncover HTT stimulation of DSB repair by organizing a TC-NHEJ complex that is impaired by mHTT thereby implicating dysregulation of transcription-coupled DSB repair in mHTT pathophysiology.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:label>\u2022<\/jats:label>\n                        <jats:p>BRG1 recruits HTT and NHEJ components to transcriptionally active DSBs.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u2022<\/jats:label>\n                        <jats:p>HTT joins BRG1 and PNKP to efficiently repair transcription related DSBs in brain.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u2022<\/jats:label>\n                        <jats:p>Mutant HTT impairs the functional integrity of TC-NHEJ complex for DSB repair.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:label>\u2022<\/jats:label>\n                        <jats:p>HTT expression improves DSB repair, genome integrity and phenotypes in HD flies.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.19.613927","type":"posted-content","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T21:55:13Z","timestamp":1726869313000},"source":"Crossref","is-referenced-by-count":4,"title":["Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in 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