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The APTX RNA\u2010DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and\n                    <jats:italic>APTX<\/jats:italic>\n                    human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X\u2010ray structures of APTX engaging nicked RNA\u2010DNA substrates that provide direct evidence for a wedge\u2010pivot\u2010cut strategy for 5\u2032\u2010AMP resolution shared with the alternate 5\u2032\u2010AMP processing enzymes POL\u03b2 and FEN1. Our results uncover a DNA\u2010induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X\u2010ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations.\n                  <\/jats:p>","DOI":"10.15252\/embj.201798875","type":"journal-article","created":{"date-parts":[[2018,6,22]],"date-time":"2018-06-22T03:25:31Z","timestamp":1529637931000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease"],"prefix":"10.1038","volume":"37","author":[{"given":"Percy","family":"Tumbale","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Schellenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey A","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Fairweather","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N","family":"Little","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juno","family":"Krahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Waddell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E","family":"London","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4610-8397","authenticated-orcid":false,"given":"R Scott","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,22]]},"reference":[{"key":"BFEMBJ201798875_CR1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.ymeth.2011.07.005","volume":"55","author":"PD Adams","year":"2011","unstructured":"Adams PD, Afonine PV, Bunkoczi G, Chen VB, Echols N, Headd JJ, Hung LW, Jain S, Kapral GJ, Grosse Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner RD, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH (2011) The Phenix software for automated determination of macromolecular structures. 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