{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T05:36:26Z","timestamp":1770701786219,"version":"3.49.0"},"reference-count":50,"publisher":"Proceedings of the National Academy of Sciences","issue":"3","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1998,2,3]]},"abstract":"<jats:p>\n            The mutational response of mismatch repair-deficient animals to the alkylating agent\n            <jats:italic>N<\/jats:italic>\n            -methyl-\n            <jats:italic>N<\/jats:italic>\n            -nitrosourea was evaluated by using a transgenic\n            <jats:italic>lacI<\/jats:italic>\n            reporter system. Although the mutations detected in\n            <jats:italic>MSH2<\/jats:italic>\n            heterozygotes were similar to those of controls,\n            <jats:italic>MSH2<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            animals demonstrated striking increases in mutation frequency in response to this agent. G:C to A:T transitions at GpG sites, as opposed to CpG sites, dominated the mutational spectrum of both\n            <jats:italic>MSH2<\/jats:italic>\n            <jats:sup>+\/+<\/jats:sup>\n            and\n            <jats:italic>MSH2<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            <jats:italic>N<\/jats:italic>\n            -methyl-\n            <jats:italic>N<\/jats:italic>\n            -nitrosourea -treated animals. Extrapolating to humans with hereditary non-polyposis colorectal cancer, the results suggest that\n            <jats:italic>MSH2<\/jats:italic>\n            heterozygotes are unlikely to be at increased risk of mutation, even when exposed to potent DNA methylating agents. In contrast, mismatch repair-deficient cells spontaneously arising within individuals with hereditary non-polyposis colorectal cancer would likely exhibit hypermutability in response to such mutagens, an outcome predicted to accelerate the pace of tumorigenesis.\n          <\/jats:p>","DOI":"10.1073\/pnas.95.3.1126","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:40:52Z","timestamp":1027694452000},"page":"1126-1130","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":54,"title":["Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating\u2009agent"],"prefix":"10.1073","volume":"95","author":[{"given":"Susan E.","family":"Andrew","sequence":"first","affiliation":[{"name":"Centre for Molecular Medicine and Therapeutics, and Department of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3; Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, B.P. 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France; 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