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

Mcm4 (minichromosome maintenance-deficient 4 homolog) encodes a subunit of the MCM2-7 complex (also known as MCM2-MCM7), the replication licensing factor and presumptive replicative helicase. Here, we report that the mouse chromosome instability mutation Chaos3 (chromosome aberrations occurring spontaneously 3), isolated in a forward genetic screen, is a viable allele of Mcm4. Mcm4(Chaos3) encodes a change in an evolutionarily invariant amino acid (F345I), producing an apparently destabilized MCM4. Saccharomyces cerevisiae strains that we engineered to contain a corresponding allele (resulting in an F391I change) showed a classical minichromosome loss phenotype. Whereas homozygosity for a disrupted Mcm4 allele (Mcm4(-)) caused preimplantation lethality, Mcm(Chaos3/-) embryos died late in gestation, indicating that Mcm4(Chaos3) is hypomorphic. Mutant embryonic fibroblasts were highly susceptible to chromosome breaks induced by the DNA replication inhibitor aphidicolin. Most notably, >80% of Mcm4(Chaos3/Chaos3) females succumbed to mammary adenocarcinomas with a mean latency of 12 months. These findings suggest that hypomorphic alleles of the genes encoding the subunits of the MCM2-7 complex may increase breast cancer risk.

Pubmed ID: 17143284

Authors

  • Shima N
  • Alcaraz A
  • Liachko I
  • Buske TR
  • Andrews CA
  • Munroe RJ
  • Hartford SA
  • Tye BK
  • Schimenti JC

Journal

Nature genetics

Publication Data

January 28, 2007

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM45415

Mesh Terms

  • Adenocarcinoma
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Chromosomal Instability
  • Chromosome Mapping
  • DNA Helicases
  • DNA Mutational Analysis
  • Female
  • Fetal Viability
  • Male
  • Mammary Neoplasms, Animal
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Minichromosome Maintenance Complex Component 4
  • Molecular Sequence Data
  • Sequence Homology, Amino Acid