Abstract
To expand the known spectrum of genes that maintain genome stability, we screened a recently released collection of temperature sensitive (Ts) yeast mutants for a chromosome instability (CIN) phenotype. Proteasome subunit genes represented a major functional group, and subsequent analysis demonstrated an evolutionarily conserved role in CIN. Analysis of individual proteasome core and lid subunit mutations showed that the CIN phenotype at semi-permissive temperature is associated with failure of subunit localization to the nucleus. The resultant proteasome dysfunction affects chromosome stability by impairing the kinetics of double strand break (DSB) repair. We show that the DNA repair protein Mms22 is required for DSB repair, and recruited to chromatin in a ubiquitin-dependent manner as a result of DNA damage. Moreover, subsequent proteasome-mediated degradation of Mms22 is necessary and sufficient for cell cycle progression through the G2/M arrest induced by DNA damage. Our results demonstrate for the first time that a double strand break repair protein is a proteasome target, and thus link nuclear proteasomal activity and DSB repair.
Highlights
Genomic instability is recognized as being an important predisposing condition that contributes to the development of cancer [1]
Genetic and biochemical analysis showed that Chromosome Instability (CIN) was associated with the failure of proteosomal subunits to localize to the nucleus, impaired kinetics of double strand break (DSB) repair, and failure to turnover the DNA repair protein Mms22 targeted for degradation by the proteasome
We show that mutations in the proteasome subunits rpn5DC and pup2, which cause nuclear mislocalization, are associated with impaired DSB repair
Summary
Genomic instability is recognized as being an important predisposing condition that contributes to the development of cancer [1]. Studies in yeast have shown that multiple overlapping pathways contribute to genomic stability [2]. NHEJ is a mechanism able to join DNA ends with no or minimal homology [6]. Recent studies suggest a role for the proteasome in DSB repair pathways: The Sem1/DSS1 protein is a newly identified subunit of the 19S proteasome in both yeast and human cells. Sem is recruited to DSB sites with the 19S and 20S proteasome particles, and is required for efficient repair of DSBs by HR and NHEJ [7]. Human DSS1 physically binds to the breast cancer susceptibility protein BRCA2, that plays an integral role in the repair of DSBs, and is required for its stability and function and for efficient formation of RAD51 nucleofilaments [8,9]
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