Aneuploidy affects DNA metabolism and segregation to cause genomic instability

描述(申请人提供)：本提案中描述的工作旨在解决这样的假设，即非整倍体通过影响DNA代谢和/或染色体分离而促进基因组的不稳定性。我们建议使用非整倍体酵母菌株，它们都表现出不同形式的基因组不稳定性，以确定细胞生理学的哪些方面对这种表型有贡献。DNA新陈代谢的缺陷，包括复制和修复，以及染色体分离机制的缺陷，都会对基因组的稳定性产生负面影响。因此，如果非整倍体本身足以导致基因组不稳定，那么确定受影响的确切过程是至关重要的，而且该提案的具体目标涉及主要目标。由于基因组改变和随后的突变积累推动了肿瘤的形成，如果非整倍体足以通过我们计划研究的过程导致基因组的不稳定，这将为揭示非整倍体在肿瘤发生中的作用提供新的线索，并为潜在的新的治疗药物打开大门，这些药物可能特异性地针对非整倍体细胞中优先受到影响的过程。

DESCRIPTION (provided by applicant): The work described within this proposal intends to address the hypothesis that aneuploidy promotes genomic instability through affecting DNA metabolism and/or chromosome segregation. We propose to use aneuploid yeast strains, which all exhibit various forms of genomic instability, to determine which aspects of cellular physiology contribute to this phenotype. Defects in DNA metabolism, including replication and repair, as well as defects in the chromosome segregation machinery can negatively impact genomic stability. Thus, if aneuploidy itself is sufficient to cause genomic instability, it is crucial to determine the exact processes affected, and the specific aims of the proposal address prime targets. Since genomic alteration and the subsequent accumulation of mutations drive the formation of tumors, if aneuploidy is sufficient to cause genomic instability through the processes we plan to investigate, it would shed new light into aneuploidy's role in tumorigenesis and also open the door for potential new therapeutic agents that might specifically target processes preferentially affected in aneuploid cells.