{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:11:17Z","timestamp":1789074677297,"version":"build-2803163510"},"reference-count":0,"publisher":"Cold Spring Harbor Laboratory","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM132128"],"award-info":[{"award-number":["R01GM132128"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM139508"],"award-info":[{"award-number":["R35GM139508"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA282733"],"award-info":[{"award-number":["R01CA282733"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM160854"],"award-info":[{"award-number":["R01GM160854"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01CA092584"],"award-info":[{"award-number":["P01CA092584"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society Research Scholar","doi-asserted-by":"publisher","award":["RSG-18-156-01-DMC"],"award-info":[{"award-number":["RSG-18-156-01-DMC"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society Research Scholar","doi-asserted-by":"publisher","award":["Barnard Foundation"],"award-info":[{"award-number":["Barnard Foundation"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society Research Scholar","doi-asserted-by":"publisher","award":["Siteman Cancer Center"],"award-info":[{"award-number":["Siteman Cancer Center"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"accepted":{"date-parts":[[2026,7,22]]},"abstract":"<jats:p>\n                    Alkylation chemotherapy is commonly used against tumors such as glioblastoma, yet resistance often develops through downregulation of mismatch repair (MMR). Previous work has established that loss of MMR prevents the excision of the thymine-containing strand across\n                    <jats:italic>O<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    meG-T mismatches, thereby avoiding the futile repair cycle that ultimately leads to cell death. Here, we provide an alternative explanation to this prevailing mechanism of chemoresistance by MMR loss. We found that the MMR protein MutL\u03b1 physically and functionally interacts with the base excision repair (BER) enzyme methylpurine DNA glycosylase (MPG), which processes common alkylation adducts, such as 7meG and 3meA. Biochemical reconstitution demonstrates that MutL\u03b1 activates MPG glycosylase activity by promoting MPG substrate binding, and enhancing MPG release from the abasic site product, thereby facilitating enzyme turnover. This glycosylase stimulation requires ATP hydrolysis as well as the MLH1-interacting region on MPG. Both MutL\u03b1 or its ability to interact with MPG promote the generation of alkylation-induced abasic sites in cells, which contribute to the cytotoxicity of methyl methanesulfonate (MMS), an S\n                    <jats:sub>N<\/jats:sub>\n                    2 alkylating agent that does not produce\n                    <jats:italic>O<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    meG. Our results provide new insight into the mechanism of alkylation chemoresistance and uncover an unappreciated cross-talk between MMR and BER.\n                  <\/jats:p>","DOI":"10.1101\/gad.353661.126","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:50:12Z","timestamp":1789073412000},"source":"Crossref","is-referenced-by-count":0,"title":["Human MutL\u03b1 activates methylpurine DNA glycosylase to induce alkylation damage cytotoxicity"],"prefix":"10.1101","author":[{"given":"Mohamed E.","family":"Ashour","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellissa","family":"Krekeler","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika Chandan","family":"Bhowmik","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holland","family":"Kantar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Tsao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Herrera-Mont\u00e1vez","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaw-Sheue","family":"Tsai","sequence":"additional","affiliation":[{"name":"Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Zaher","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyudmila Y.","family":"Kadyrova","sequence":"additional","affiliation":[{"name":"Division of Biochemistry and Molecular Biology, Department of Biomedical Sciences, Southern Illinois University School of Medicine, Carbondale, Illinois 62901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid A.","family":"Kadyrov","sequence":"additional","affiliation":[{"name":"Division of Biochemistry and Molecular Biology, Department of Biomedical Sciences, Southern Illinois University School of Medicine, Carbondale, Illinois 62901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Galletto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5453-5914","authenticated-orcid":false,"given":"Nima","family":"Mosammaparast","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2026,9,10]]},"container-title":["Genes &amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/gad.353661.126","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:50:12Z","timestamp":1789073412000},"score":1,"resource":{"primary":{"URL":"http:\/\/genesdev.cshlp.org\/lookup\/doi\/10.1101\/gad.353661.126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":0,"alternative-id":["10.1101\/gad.353661.126"],"URL":"https:\/\/doi.org\/10.1101\/gad.353661.126","relation":{},"ISSN":["0890-9369","1549-5477"],"issn-type":[{"value":"0890-9369","type":"print"},{"value":"1549-5477","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}