{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:51:47Z","timestamp":1785408707236,"version":"3.56.0"},"reference-count":63,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["25-24-00148"],"award-info":[{"award-number":["25-24-00148"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25-24-00148"],"award-info":[{"award-number":["25-24-00148"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Human alkyladenine DNA glycosylase (AAG) initiates base excision repair of various alkylated and deaminated purines. Single nucleotide polymorphisms (SNPs) in the AAG gene occur frequently in populations and tumors, but the functional impact of most variants remains unknown. Previously, we identified three SNPs\u2014P94L, V158M, and E293K\u2014which have been predicted to have a high deleterious potential. This study aimed to characterize their biochemical properties and structural consequences. Using a combination of biochemical assays and molecular dynamics simulations, we assessed the thermal stability, DNA binding affinity, and catalytic activity of these mutants on two structurally distinct substrates: 1, N6-ethenoadenosine (\u03b5A) and hypoxanthine (Hx). All three mutants exhibited reduced melting temperatures, indicating pronounced destabilization. Despite this, their DNA-binding affinities remained close to WT AAG. Strikingly, the mutants displayed differential loss of catalytic activity: P94L was inactive against both \u03b5A and Hx; V158M retained activity against \u03b5A but lost activity against Hx; and E293K was active against Hx but inactive against \u03b5A. MD simulations revealed that P94L alters the flexible R138\u2013T143 loop, V158M narrows the active site cleft, and E293K disrupts a C-terminal salt bridge while increasing DNA engagement by the positively charged tail. These findings demonstrate that non-active-site SNPs can qualitatively reprogram the substrate specificity of AAG. These variants could be considered as potential functional biomarkers for cancer risk and response to alkylating chemotherapy.<\/jats:p>","DOI":"10.3390\/ijms27156595","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"6595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Substrate-Specific Inactivation of Human AAG by Tumor-Associated Single Nucleotide Polymorphic Variants"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4157-5244","authenticated-orcid":false,"given":"Olga A.","family":"Kladova","sequence":"first","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timofey E.","family":"Tyugashev","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3408-261X","authenticated-orcid":false,"given":"Artemiy S.","family":"Bakman","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-7050","authenticated-orcid":false,"given":"Aleksandra A.","family":"Kuznetsova","sequence":"additional","affiliation":[{"name":"Knorre Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/362709a0","article-title":"Instability and Decay of the Primary Structure of DNA","volume":"362","author":"Lindahl","year":"1993","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Basu, A.K. 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