Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level

Sasatani, Megumi; Xi, Yang; Kajimura, Junko; Kawamura, Toshijiro; Piao, Jinlian; Masuda, Yuji; Honda, Hiroaki; Kubo, Katsumaro; Mikamoto, Takahiro; Watanabe, Haruo; Xu, Yujia; Kawai, Hidehiko; Shimura, Tsutomu; Noda, Asao; Hamasaki, Koji; Kusunoki, Yoichiro; Zaharieva, Elena Karamfilova; Kamiya, Kenji

doi:10.1093/carcin/bgw208

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…Additionally, these differences in mutation signature may be due to low (or no) Rev1 translesion 5 DNA synthesis in colon tissue, which is the only DNA polymerase known to insert cytosine nucleobases opposite abasic sites (Lawrence, 2002). In support, Rev1 overexpression was necessary to stimulate polyp formation and enhance mutagenesis in an MNU-dependent murine intestinal adenoma model (Sasatani et al, 2017).…”

Section: Discussionmentioning

confidence: 85%

APOBEC3A Catalyzes Mutation and Drives CarcinogenesisIn Vivo

Law

Levin‐Klein

Jarvis

et al. 2019

Preprint

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The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other 5 APOBEC3 family members including APOBEC3B did not as strongly promote liver tumor formation. DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in 10 human tumor data sets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.

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Section: Discussionmentioning

confidence: 85%

APOBEC3A Catalyzes Mutation and Drives CarcinogenesisIn Vivo

Law

Levin‐Klein

Jarvis

et al. 2019

Preprint

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“…Here we have introduced several mouse models with disruptions in Rev1 functions, including the Rev1 Tg mouse model generated in our laboratory. Recently we have reported that in Rev1 Tg mice the elevated Rev1 expression allows cells with mutations to survive after DNA damages, resulting in an acceleration of tumorigenesis [47,48]. However, in vivo data like this is almost completely absent from the literature.…”

Section: Discussionmentioning

confidence: 98%

“…No significant effect on overall survival or tumor incidence was observed, suggesting that overexpression of Rev1 by itself is not sufficient to stimulate tumorigenesis. However, our study revealed that overexpression of Rev1 promotes development of chemically-induced tumors, namely azoxymethane (AOM)-induced hepatocellular carcinoma, and N-methyl-N-nitrosourea (MNU)-induced thymic lymphoma and intestinal adenomas (Sasatani et al, manuscript in preparation) [47,48]. Furthermore, in a comparative analysis of MNU-induced carcinogenesis in Rev1 Tg (Homo) mice, which are homozygous (Tg+/Tg+) for the Rev1 transgene, versus heterozygous Rev1 Tg mice, we provided evidence that Rev1 overexpression accelerates tumorigenesis in proportion to the Rev1 expression level.…”

Section: Rev1 Tg Micementioning

confidence: 93%

“…Rev1 Tg mice were generated in our laboratory by using the metallothionein promoter 1 (MT-1) to achieve inducible expression [47]. We found that the Rev1 transgene was expressed at low levels in the liver and kidney, but at dramatically higher levels in the thymus, spleen, and lymph nodes.…”

Section: Rev1 Tg Micementioning

confidence: 99%

“…Overexpressed Rev1 suppresses apoptosis and increases the mutation frequency after the treatment of chemical reagents. The surviving fraction of mutated cells was higher under Rev1 overexpression, resulting in acceleration of carcinogenesis phenotype, with enhanced mutation frequency and hindered cell death, therefore, it can be clearly stated that regulation of Rev1 levels is required for maintaining genomic stability and tumor suppression(Table 2)[47].…”

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confidence: 99%

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The in vivo role of Rev1 in mutagenesis and carcinogenesis

2020

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Translesion synthesis (TLS) is an error-prone pathway required to overcome replication blockage by DNA damage. Aberrant activation of TLS has been suggested to play a role in tumorigenesis by promoting genetic mutations. However, the precise molecular mechanisms underlying TLS-mediated tumorigenesis in vivo remain unclear. Rev1 is a member of the Y family polymerases and plays a key role in the TLS pathway. Here we introduce the existing to date Rev1-mutated mouse models, including the Rev1 transgenic (Tg) mouse model generated in our laboratory. We give an overview of the current knowledge on how different disruptions in Rev1 functions impact mutagenesis and the suggested molecular mechanisms underlying these effects. We summarize the available data from ours and others' in vivo studies on the role of Rev1 in the initiation and promotion of cancer, emphasizing how Rev1-mutated mouse models can be used as complementary tools for future research.

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Regulation of the abundance of Y-family polymerases in the cell cycle of budding yeast in response to DNA damage

et al. 2020

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Y-family DNA polymerases mediate DNA damage tolerance via translesion synthesis (TLS). Because of the intrinsically error-prone nature of these enzymes, their activities are regulated at several levels. Here, we demonstrate the common regulation of the cellular abundance of Y-family polymerases, polymerase eta (Pol eta), and Rev1, in response to DNA damage at various stages of the cell cycle. UV radiation influenced polymerase abundance more when cells were exposed in S-phase than in G1-or G2-phases. We noticed two opposing effects of UV radiation in S-phase. On one hand, exposure to increasing doses of UV radiation at the beginning of this phase increasingly delayed S-phase progression. As a result, the accumulation of Pol eta and Rev1, which in nonirradiated yeast is initiated at the S/G2-phase boundary, was gradually shifted into the prolonged S-phase. On the other hand, the extent of polymerase accumulation was inversely proportional to the dose of irradiation, such that the accumulation was significantly lower after exposure to 80 J/m 2 in S-phase than after exposure to 50 J/m 2 or 10 J/m 2 . The limitation of polymerase accumulation in S-phase-arrested cells in response to high UV dose was suppressed upon RAD9 (but not MRC1) deletion. Additionally, hydroxyurea, which activates mainly the Mrc1-dependent checkpoint, did not limit Pol eta or Rev1 accumulation in S-phase-arrested cells. The results show that the accumulation of Y-family TLS polymerases is limited in S-phase-arrested cells due to high levels of DNA damage and suggest a role of the Rad9 checkpoint protein in this process.Keywords Polymerase eta · Rev1 · Y-family polymerases · S-phase checkpoint · DNA damage response · S. cerevisiae Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Overexpression of Rev1 promotes the development of carcinogen-induced intestinal adenomas via accumulation of point mutation and suppression of apoptosis proportionally to the Rev1 expression level

Cited by 19 publications

References 45 publications

APOBEC3A Catalyzes Mutation and Drives CarcinogenesisIn Vivo

APOBEC3A Catalyzes Mutation and Drives CarcinogenesisIn Vivo

The in vivo role of Rev1 in mutagenesis and carcinogenesis

Regulation of the abundance of Y-family polymerases in the cell cycle of budding yeast in response to DNA damage

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