{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T14:10:11Z","timestamp":1776003011690,"version":"3.50.1"},"posted":{"date-parts":[[2024,10,7]]},"group-title":"Biochemistry","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000},"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":[[2024,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>FAN1 is a DNA dependent nuclease whose proper function is essential for maintaining human health. For example, a genetic variant in FAN1, Arg507 to His hastens onset of Huntington\u2019s disease, a repeat expansion disorder for which there is no cure. How the Arg507His mutation affects FAN1 structure and enzymatic function is unknown. Using cryo-EM and biochemistry, we have discovered that FAN1 arginine 507 is critical for its interaction with PCNA, and mutation of Arg507 to His attenuates assembly of the FAN1-PCNA on a disease-relevant extrahelical DNA extrusions formed within DNA repeats. This mutation concomitantly abolishes PCNA-FAN1-dependent cleavage of such extrusions, underscoring the importance of PCNA to the genome stabilizing function of FAN1. These results unravel the molecular basis for a specific mutation in FAN1 that dramatically hastens the onset of Huntington\u2019s disease.<\/jats:p>","DOI":"10.1101\/2024.10.07.617005","type":"posted-content","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T01:00:18Z","timestamp":1728349218000},"source":"Crossref","is-referenced-by-count":2,"title":["Structural and molecular basis of FAN1 defects in promoting Huntington\u2019s disease"],"prefix":"10.64898","author":[{"given":"F.","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Phadte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Barndt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"A. 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