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Title: Rev1 overexpression accelerates N-methyl-N-nitrosourea (MNU)-induced thymic lymphoma by increasing mutagenesis

Journal Article · · Cancer Science
DOI: https://doi.org/10.1111/cas.16159 · OSTI ID:2470366
ORCiD logo [1];  [2];  [3];  [3];  [4];  [5];  [1];  [1]; ORCiD logo [6];  [1];  [7];  [7];  [8]; ORCiD logo [3];  [9];  [3];  [10];  [1];  [1]
  1. Hiroshima Univ. (Japan)
  2. Hiroshima Univ. (Japan); Ningbo University (China)
  3. National Institutes for Quantum Science and Technology, Chiba (Japan)
  4. Hiroshima Univ. (Japan); Nagoya Univ. (Japan)
  5. Hiroshima Univ. (Japan); Radiation Effects Research Foundation (RERF), Hiroshima (Japan)
  6. Tokyo Women's Medical University (Japan)
  7. Radiation Effects Research Foundation (RERF), Hiroshima (Japan)
  8. National Institute of Public Health, Saitama (Japan)
  9. Institute for Environmental Sciences, Aomori (Japan)
  10. Osaka Univ. (Japan)
+ Show Author Affiliations

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.

Research Organization:
Radiation Effects Research Foundation (RERF), Hiroshima (Japan)
Sponsoring Organization:
USDOE
OSTI ID:
2470366
Journal Information:
Cancer Science, Journal Name: Cancer Science Journal Issue: 6 Vol. 115; ISSN 1347-9032
Publisher:
The Japanese Cancer AssociationCopyright Statement
Country of Publication:
United States
Language:
English

References (51)

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Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells journal October 2021
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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 journal May 2017
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Involvement of Rev1 in alkylating agent‐induced loss of heterozygosity in Oryzias latipes journal February 2020
Radiation sensitivity and genomic instability in the hematopoietic system: Frequencies of micronucleated reticulocytes in whole-body X-irradiated BALB/c and C57BL/6 mice journal December 2007
Bcl11b heterozygosity promotes clonal expansion and differentiation arrest of thymocytes in γ‐irradiated mice journal May 2010
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Identification of a novel REV1-interacting motif necessary for DNA polymerase κ function journal February 2009
Suppression of hREV1 Expression Reduces the Rate at Which Human Ovarian Carcinoma Cells Acquire Resistance to Cisplatin journal March 2005
Human REV1 Modulates the Cytotoxicity and Mutagenicity of Cisplatin in Human Ovarian Carcinoma Cells journal February 2006
Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability journal June 2020
Specialized DNA Polymerases, Cellular Survival, and the Genesis of Mutations journal May 2002
Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance journal April 2020
Complex Formation with Rev1 Enhances the Proficiency of Saccharomyces cerevisiae DNA Polymerase ζ for Mismatch Extension and for Extension Opposite from DNA Lesions journal December 2006
Yeast DNA Polymerase ζ Is an Efficient Extender of Primer Ends Opposite from 7,8-Dihydro-8-Oxoguanine and O6-Methylguanine journal February 2003
Multiple Roles of Vertebrate REV Genes in DNA Repair and Recombination journal July 2005
EUKARYOTIC TRANSLESION SYNTHESIS DNA POLYMERASES: Specificity of Structure and Function journal June 2005
Whole-Exome Sequencing of Radiation-Induced Thymic Lymphoma in Mouse Models Identifies Notch1 Activation as a Driver of p53 Wild-Type Lymphoma journal May 2021
REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer journal February 2009
Mutational landscape in genetically engineered, carcinogen-induced, and radiation-induced mouse sarcoma journal July 2019
The in vivo role of Rev1 in mutagenesis and carcinogenesis journal February 2020
Spectrum of Znfn1a1 (Ikaros) Inactivation and its Association with Loss of Heterozygosity in Radiogenic T-Cell Lymphomas in Susceptible B6C3F1 Mice journal March 2002
The ubiquitous ‘cancer mutational signature’ 5 occurs specifically in cancers with deleted FHIT alleles journal November 2017
A Critical Role for REV1 in Regulating the Induction of C:G Transitions and A:T Mutations during Ig Gene Hypermutation journal August 2009
NK-Mediated Elimination of Mutant Lymphocytes that Have Lost Expression of MHC Class I Molecules journal October 2000

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Related Subjects

60 APPLIED LIFE SCIENCES
DNA translesion synthesis
mutagenesis
thymic lymphoma
tumorigenesis
whole-exome sequencing