Role of DNA Replication Defects in Breast Cancer
Annual summary rept. 1 Oct 2008-30 Sep 2009
CORNELL UNIV ITHACA NY
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Several recent studies have indicated that decreased levels of the MCM2-7 DNA replication proteins can lead to genomic instability GIN and cancer formation. Interestingly, genetic or RNAi-mediated depletion of one MCM has been demonstrated to cause decreases in other MCMs, presumably as a consequence of MCM heterohexamer destabilization. In the first year of my training grant, my research results show that in cells bearing only the Mcm4Chaos3 cancer susceptibility allele, the cause for reduced MCM protein levels is related to decreased Mcm2-7 and 10 mRNA. Despite being present at levels far exceeding that required for DNA replication under normal circumstances, we found that heterozygosity for 2 or more different MCMs caused genomic instability, and in the cases of MCM2, MCM6 and MCM7, synthetic lethality in conjunction with Mcm4Chaos3 homozygosity. These data suggest that proper stoichemistry of MCM components is carefully regulated, and that relatively minor disregulation or destabilization of MCM levels can have serious consequences for survival or cancer susceptibility in whole animals.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research