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

J M M van Oers1, Y Edwards1, R Chahwan1

  • 1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.

Oncogene
|September 10, 2013
PubMed

Insights

Loss of MSH3 protein impacts tumor development and progression. The MSH2-MSH3 complex suppresses chromosomal instability and modulates p53-driven cancer, highlighting its role in DNA repair and mismatch repair.

Area of Science:

  • Genetics
  • Cancer Biology
  • Molecular Biology

Background:

  • Loss of DNA mismatch repair (MMR) protein MSH3 is linked to various tumors.
  • The MutSβ (MSH2-MSH3) complex may modulate late-onset tumorigenesis.
  • MSH3's specific role in tumor progression requires further investigation.

Purpose of the Study:

  • To investigate the role of MSH3 in p53-driven tumorigenesis.
  • To determine MSH3's impact on DNA double-strand break repair (DSBR) and chromosomal stability.
  • To elucidate the function of the MSH2-MSH3 complex in suppressing tumor development.

Main Methods:

  • Crossed Msh3(-/-) mice with p53-deficient mice.
  • Analyzed survival rates and tumor spectrum.
  • Assessed DNA double-strand break repair (DSBR) in mouse embryonic fibroblasts.
  • Examined genomic alterations (LOH, CNV, MSI) in tumors.

Main Results:

  • Msh3/p53 mice showed a shift from lymphoma to sarcoma, indicating MSH3 modulates p53-driven tumorigenesis.
  • Msh3(-/-) fibroblasts exhibited defects in DSBR, evidenced by increased chromatid breaks and persistent γH2AX foci.
  • Msh3/p53 tumors displayed increased LOH and CNV, with a moderate MSI phenotype compared to Msh2/p53 tumors.
  • MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability.

Conclusions:

  • The MSH2-MSH3 complex is crucial for suppressing late-onset tumors via DNA DSBR and MMR.
  • MSH2-MSH3 inhibits chromosomal instability and influences the tumor spectrum in p53-deficient contexts.
  • MSH2-MSH3 may play a role in other chromosomally unstable tumors.

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