Rev1 overexpression accelerates N-methyl-N-nitrosourea (MNU)-induced thymic lymphoma by increasing mutagenesis.
Megumi SasataniYang XiKazuhiro DainoAtsuko IshikawaYuji MasudaJunko KajimuraJinlian PiaoElena Karamfilova ZaharievaHiroaki HondaGuanyu ZhouKanya HamasakiYoichiro KusunokiTsutomu ShimuraShizuko KakinumaYoshiya ShimadaKazutaka DoiTomoko Ishikawa-FujiwaraYusuke SotomaruKenji KamiyaPublished in: Cancer science (2024)
Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg 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 Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.
Keyphrases
- wild type
- high glucose
- dna damage
- crispr cas
- diabetic rats
- oxidative stress
- genome wide
- drug induced
- high fat diet induced
- risk factors
- cell proliferation
- diffuse large b cell lymphoma
- metabolic syndrome
- gene expression
- copy number
- young adults
- type diabetes
- small molecule
- skeletal muscle
- endothelial cells
- insulin resistance
- single cell
- adipose tissue
- papillary thyroid
- cell death
- cell cycle arrest
- smoking cessation
- combination therapy
- binding protein