Aneuploidy Pathways for Inducible Chromosome Missegregation (360G-Wellcome-325314_Z_25_Z)

This proposal will examine Chromosome INstability (CIN) as an adaptive stress response, rather than a mitotic error. When exposed to stress, fungi elevate the rate of CIN, generating new aneuploid karyotypes, which are adaptive in different stress conditions. Therefore, chromosome missegregation can be beneficial, and used as a tool of adaptation. Mechanisms by which stress results in elevated CIN are poorly understood. Through candidate and screening approaches, we will identify genomic loci and pathways responsible for elevating CIN in stress. These “aneuploidy switches" and "aneuploidy pathways” would function as mirror opposites of mitotic stability genes, enabling elevated CIN and increased karyotype variance in a changing environment. In a targeted approach, we will explore the role of introns and pre-mRNA processing in elevated CIN and adaptability of S.cerevisiae and C.albicans. These fungi contain introns in genes essential for accurate mitosis, making chromosome segregation vulnerable to altered pre-mRNA processing which occurs in stress. Additionally, we will use the power of genome-wide yeast screens to identify novel factors which alter mitotic stability in stress. This project will radically change our view of mitosis, as a process whose fidelity can be actively downregulated by the cell, in favour of karyotype variance and adaptability.