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- Title
A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice.
- Authors
Shima, Naoko; Alcaraz, Ana; Liachko, Ivan; Buske, Tavanna R.; Andrews, Catherine A.; Munroe, Robert J.; Hartford, Suzanne A.; Tye, Bik K.; Schimenti, John C.
- 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. Mcm4Chaos3 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, McmChaos3/− embryos died late in gestation, indicating that Mcm4Chaos3 is hypomorphic. Mutant embryonic fibroblasts were highly susceptible to chromosome breaks induced by the DNA replication inhibitor aphidicolin. Most notably, >80% of Mcm4Chaos3/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.
- Subjects
CHROMOSOME abnormalities; CHROMATIN; GENE mapping; BREAST cancer risk factors; SACCHAROMYCES cerevisiae
- Publication
Nature Genetics, 2007, Vol 39, Issue 1, p93
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1936