期刊
PLOS GENETICS
卷 6, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1000852
关键词
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资金
- National Institutes of Health (NIH) [P01 CA16519]
- Canadian Institute for Health Research, (CIHR) [MOP-38096]
- NIH roadmap [U54 RR020839]
- Human Frontier Science Program (HFSP)
- Killam trust
- Israel Science Foundation
- US-Israel Bi-national Fund (BSF)
- Association for International Cancer Research (AICR)
- Israeli Ministry of Science, Culture, and Sport
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 G(2)/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.
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