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However, the role of Rev1 in mutagenesis and tumorigenesis in\u00a0vivo remains unclear. We previously generated <jats:italic>Rev1<\/jats:italic>\u2010overexpressing (<jats:italic>Rev1<\/jats:italic>\u2010Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:italic>N<\/jats:italic>\u2010nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU\u2010induced TL tumorigenesis in wild\u2010type (WT) and <jats:italic>Rev1<\/jats:italic>\u2010Tg mice using diverse approaches, including whole\u2010exome sequencing (WES). In <jats:italic>Rev1<\/jats:italic>\u2010Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and <jats:italic>Rev1<\/jats:italic>\u2010Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging\u2010related) and SBS11 (alkylation\u2010related). Interestingly, the total number of mutations, but not the genotypes of WT and <jats:italic>Rev1<\/jats:italic>\u2010Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in <jats:italic>Rev1<\/jats:italic>\u2010Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in <jats:italic>Rev1<\/jats:italic>\u2010Tg mice than in WT mice, following MNU treatment. In conclusion, <jats:italic>Rev1<\/jats:italic> overexpression accelerates mutagenesis and increases the incidence of MNU\u2010induced TL by shortening the latency period, which may be associated with more frequent DNA damage\u2010induced genetic instability.<\/jats:p>","DOI":"10.1111\/cas.16159","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T07:49:58Z","timestamp":1712216998000},"page":"1808-1819","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>Rev1<\/i> overexpression accelerates <i>N<\/i>\u2010methyl\u2010<i>N<\/i>\u2010nitrosourea (MNU)\u2010induced thymic lymphoma by increasing mutagenesis"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1219-1014","authenticated-orcid":false,"given":"Megumi","family":"Sasatani","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology Research Institute for Radiation Biology 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