Title

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

Document Type

Article

Publication Date

2007

Keywords

Amino-Acid-Sequence, Animals, Cells-Cultured, Chromosomal-Instability, Chromosome-Mapping, DNA-Helicases, DNA-Mutational-Analysis, Female, Fetal-Viability, Male, Mammary-Neoplasms-Animal, Mice-Inbred-C3H, Mice-Inbred-C57BL, Mice-Transgenic, Molecular-Sequence-Data, Sequence-Homology-Amino-Acid

JAX Source

Nat Genet 2007 Jan; 39(1):93-8.

Abstract

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.