Aneuploidy affects DNA metabolism and segregation to cause genomic instability

描述（由申请人提供）：本提案中描述的工作旨在解决非整倍性通过影响DNA代谢和/或染色体分离促进基因组不稳定性的假设。我们建议使用非整倍体酵母菌株，这都表现出各种形式的基因组不稳定性，以确定哪些方面的细胞生理有助于这种表型。DNA代谢的缺陷，包括复制和修复，以及染色体分离机制的缺陷可能会对基因组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性，那么确定受影响的确切过程至关重要，并且该提案的具体目标针对主要目标。由于基因组改变和随后的突变积累驱动肿瘤的形成，如果非整倍性足以通过我们计划研究的过程引起基因组不稳定性，它将为非整倍性在肿瘤发生中的作用提供新的线索，并为潜在的新治疗药物打开大门，这些药物可能特异性靶向非整倍体细胞中优先受影响的过程。 公共卫生相关性：这里提出的研究旨在深入了解非整倍体在人类疾病中的作用，特别是癌症。非整倍体与癌症密切相关，尽管其作用尚不清楚。确定非整倍性细胞生理学的影响，特别是其对基因组稳定性的影响，不仅有助于确定癌症的可能原因，而且还为新的治疗药物提供了靶点。

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. PUBLIC HEALTH RELEVANCE: The research proposed here seeks to gain insight into the role that aneuploidy plays in human disease, specifically cancer. Aneuploidy is strongly correlated with cancer, though its role remains unclear. Determining the effects of aneuploidy cellular physiology, particularly its effect on genomic stability, will not only help determine a possible cause of cancer but also provide a target for new therapeutic agents.