MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Aneuploidy is the leading cause of miscarriages in humans and a hallmark of cancer. Determining the origins and effects of aneuploidy is thus vital for understanding the principles underlying tumor formation and infertility. We had previously examined the effects of aneuploidy on yeast cells and found the condition to cause a proliferation defect and a set of phenotypes that is independent of the identity of the additional chromosome. Our working hypothesis was and continues to be that some aspect of aneuploidy (i.e. stress on the protein synthesis, turn-over and/or folding machinery) elicits a response that is not unlike a stress response and results in a proliferation defect. Most tumor cells are aneuploid suggesting that aneuploidy plays an important role in tumor formation. Mutations that suppress the proliferation defects caused by aneuploidy will therefore shed light on how tumors evolve. In Specific Aim 3 of the parent proposal and in the extended version thereof described in the Supplemental Application we proposed to identify mutations that suppress the proliferation defect of aneuploid yeast cells. The characterization of such aneuploidy-tolerating mutations will likely provide vital insights into the mechanisms of tumorigenesis.