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

Naoko Shima, Ana Alcaraz, Ivan Liachko, Tavanna R. Buske, Catherine A. Andrews, Robert J. Munroe, Suzanne A. Hartford, Bik K. Tye, John C. Schimenti

Research output: Contribution to journalArticle

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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, 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 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.

Original languageEnglish (US)
Pages (from-to)93-98
Number of pages6
JournalNature Genetics
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2007

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    Shima, N., Alcaraz, A., Liachko, I., Buske, T. R., Andrews, C. A., Munroe, R. J., Hartford, S. A., Tye, B. K., & Schimenti, J. C. (2007). A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nature Genetics, 39(1), 93-98. https://doi.org/10.1038/ng1936