The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair

J. M M Van Oers, Y. Edwards, R. Chahwan, W. Zhang, C. Smith, X. Pechuan, S. Schaetzlein, B. Jin, Yanhua Wang, Aviv Bergman, Matthew D. Scharff, Winfried Edelmann

Research output: Contribution to journalArticle

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Abstract

Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3 -/- mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared with p53 single mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3 -/- mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double-strand break repair (DSBR). Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy-number variation and a moderate microsatellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR. Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.

Original languageEnglish (US)
Pages (from-to)3939-3946
Number of pages8
JournalOncogene
Volume33
Issue number30
DOIs
StatePublished - Jul 24 2014

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DNA Mismatch Repair
Double-Stranded DNA Breaks
Carcinogenesis
Neoplasms
Chromosomal Instability
Microsatellite Instability
Chromatids
Loss of Heterozygosity
Ionizing Radiation
Sarcoma
Lymphoma
Fibroblasts
Genome
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair. / Van Oers, J. M M; Edwards, Y.; Chahwan, R.; Zhang, W.; Smith, C.; Pechuan, X.; Schaetzlein, S.; Jin, B.; Wang, Yanhua; Bergman, Aviv; Scharff, Matthew D.; Edelmann, Winfried.

In: Oncogene, Vol. 33, No. 30, 24.07.2014, p. 3939-3946.

Research output: Contribution to journalArticle

Van Oers, J. M M ; Edwards, Y. ; Chahwan, R. ; Zhang, W. ; Smith, C. ; Pechuan, X. ; Schaetzlein, S. ; Jin, B. ; Wang, Yanhua ; Bergman, Aviv ; Scharff, Matthew D. ; Edelmann, Winfried. / The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair. In: Oncogene. 2014 ; Vol. 33, No. 30. pp. 3939-3946.
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