{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:28Z","timestamp":1789020448184,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100016229","name":"Basic Research Laboratory","doi-asserted-by":"publisher","award":["1ZIABC012091"],"award-info":[{"award-number":["1ZIABC012091"]}],"id":[{"id":"10.13039\/100016229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"abstract":"<jats:p>\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132 mutations are among the most frequent hotspot mutations in cancer, but their mutational origins have remained unclear. Here, we provide evidence that\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132C, the predominant\n                    <jats:italic>IDH1<\/jats:italic>\n                    mutation in cholangiocarcinoma, acute myeloid leukemia, and melanoma, likely arises through\u00a0APOBEC3\u2010mediated mutagenesis, specifically by APOBEC3A or\u00a0APOBEC3B.\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132C is a TpC&gt;TpT substitution on the lagging\u2010strand DNA template within a hairpin\u2010forming sequence context, consistent with APOBEC3 susceptibility.\n                    <jats:italic>In vitro<\/jats:italic>\n                    assays showed that APOBEC3A and APOBEC3B can deaminate the relevant cytosine, while\n                    <jats:italic>APOBEC3A<\/jats:italic>\n                    and\n                    <jats:italic>APOBEC3B<\/jats:italic>\n                    expression patterns in tumor types with recurrent\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132C were consistent with their potential involvement in generating this mutation.\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132G, a TpC&gt;TpG substitution at the same site, may similarly result from APOBEC3A or APOBEC3B activity. By contrast,\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132H, the predominant\n                    <jats:italic>IDH1<\/jats:italic>\n                    mutation in lower grade glioma and glioblastoma, is a CpG&gt;TpG substitution at a methylated cytosine on the leading\u2010strand DNA template, a pattern more consistent with DNA polymerase epsilon replication error. Concordantly, tumor types enriched for\n                    <jats:italic>IDH1<\/jats:italic>\n                    R132H showed relatively low\n                    <jats:italic>POLE<\/jats:italic>\n                    expression. Together, these\n                    <jats:italic>in vitro<\/jats:italic>\n                    and bioinformatic analyses provide insight into the distinct mutational mechanisms that likely underlie recurrent\n                    <jats:italic>IDH1<\/jats:italic>\n                    hotspot mutations in cancer.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70334","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:55:07Z","timestamp":1789019707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>APOBEC3<\/scp>\n                    activity and\n                    <scp>DNA<\/scp>\n                    polymerase\u2010\u03b5 deficiency are associated with distinct\n                    <scp>\n                      <i>IDH1<\/i>\n                      R132\n                    <\/scp>\n                    hotspot mutations"],"prefix":"10.1002","author":[{"given":"Kelly E.","family":"Butler","sequence":"first","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal A.","family":"Lone","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ecem","family":"Unal","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1521-340X","authenticated-orcid":false,"given":"A. Rouf","family":"Banday","sequence":"additional","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"7793","key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","article-title":"The repertoire of mutational signatures in human cancer","volume":"578","author":"Alexandrov LB","year":"2020","journal-title":"Nature"},{"issue":"1","key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13045-023-01425-5","article-title":"APOBEC3\u2010mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential","volume":"16","author":"Butler K","year":"2023","journal-title":"J Hematol 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