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.
Shima
Naoko
N
Department of Genetics, Cell Biology and Development, College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA. shima023@umn.edu
Alcaraz
Ana
A
Liachko
Ivan
I
Buske
Tavanna R
TR
Andrews
Catherine A
CA
Munroe
Robert J
RJ
Hartford
Suzanne A
SA
Tye
Bik K
BK
Schimenti
John C
JC
D000230:Adenocarcinoma / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D002874:Chromosome Mapping; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005328:Fetal Viability / Q000235:genetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064148:Minichromosome Maintenance Complex Component 4; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid
D004265:DNA Helicases; C516793:Mcm4 protein, mouse; D064148:Minichromosome Maintenance Complex Component 4