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

• Published in: Nature genetics Vol. 39; no. 1; pp. 93 - 98
• Main Authors: Shima, Naoko, Schimenti, John C, Alcaraz, Ana, Liachko, Ivan, Buske, Tavanna R, Andrews, Catherine A, Munroe, Robert J, Hartford, Suzanne A, Tye, Bik K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-01-2007
• Subjects: Adenocarcinoma - genetics; Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Breast cancer; Care and treatment; Cells, Cultured; Chromosomal Instability - genetics; Chromosome aberrations; Chromosome Mapping; Chromosomes; Complications and side effects; Deoxyribonucleic acid; DNA; DNA Helicases - genetics; DNA Mutational Analysis; Embryos; Female; Fetal Viability - genetics; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Gynecology. Andrology. Obstetrics; Health risks; Homozygosity; Licensing; Male; Mammary gland diseases; Mammary Neoplasms, Animal - genetics; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Minichromosome Maintenance Complex Component 4; Molecular Sequence Data; Mutation; Physiological aspects; Risk factors; Rodents; Saccharomyces cerevisiae; Sequence Homology, Amino Acid; Tumors; United States; Mammary gland diseases; Vertebrata; Allele; Mammalia; Mouse; Breast adenocarcinoma; Rodentia; Chromosome; Instability; Malignant tumor
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1936

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.