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A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice

Naoko Shima1, Ana Alcaraz, Ivan Liachko

  • 1Department of Genetics, Cell Biology and Development, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA. shima023@umn.edu

Nature Genetics
|December 5, 2006
PubMed

Insights

The minichromosome maintenance-deficient 4 homolog (Mcm4) gene mutation Chaos3 destabilizes the MCM4 protein, leading to embryonic lethality and increased mammary tumor risk in mice.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Mcm4 is a subunit of the MCM2-7 complex, crucial for DNA replication licensing and acting as a replicative helicase.
  • The Chaos3 mutation in mice affects Mcm4, impacting chromosome stability.

Purpose of the Study:

  • To investigate the functional consequences of the Mcm4 Chaos3 mutation.
  • To determine the role of Mcm4 in embryonic development and cancer susceptibility.

Main Methods:

  • Forward genetic screen to identify the Chaos3 mutation.
  • Engineering of yeast strains with corresponding Mcm4 mutations.
  • Analysis of Mcm4(Chaos3/-) and Mcm4(Chaos3/Chaos3) mouse embryonic fibroblasts.
  • Phenotypic analysis of Mcm4(Chaos3/Chaos3) female mice.

Main Results:

  • The Chaos3 mutation (F345I) destabilizes the MCM4 protein.
  • Engineered yeast strains showed minichromosome loss.
  • Mcm4(Chaos3/-) embryos exhibited late embryonic lethality, indicating a hypomorphic allele.
  • Mutant cells were sensitive to DNA replication inhibitors.
  • Mcm4(Chaos3/Chaos3) female mice developed mammary adenocarcinomas at a high incidence.

Conclusions:

  • Hypomorphic Mcm4 alleles can cause developmental defects and embryonic lethality.
  • Mcm4 dysfunction is linked to increased susceptibility to mammary tumors.
  • These findings suggest a potential role for MCM2-7 complex subunit hypomorphic alleles in human breast cancer risk.

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