期刊
CELL CYCLE
卷 10, 期 24, 页码 4300-4310出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.24.18642
关键词
genomic stability; DNA repair; double-strand breaks; ATM; proteasome; PA28 gamma (PSME3)
类别
资金
- Israel Science Foundation
- A-T Medical Research Foundation
- Israel Cancer Research Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health (NIH) [CA 50519]
- European Community [FP7/2007-2013, HEALTH-F2-2010-259893]
- Netherlands Genomics Initiative / Netherlands Organization for Scientific Research
The DNA damage response (DDR) is a complex signaling network that leads to damage repair while modulating numerous cellular processes. DNA double-strand breaks (DSBs)-a highly cytotoxic DNA lesion-activate this system most vigorously. The DSB response network is orchestrated by the ATM protein kinase, which phosphorylates key players in its various branches. Proteasome-mediated protein degradation plays an important role in the proteome dynamics following DNA damage induction. Here, we identify the nuclear proteasome activator PA28 gamma (REG gamma; PSME3) as a novel DDR player. PA28 gamma depletion leads to cellular radiomimetic sensitivity and a marked delay in DSB repair. Specifically, PA28 gamma deficiency abrogates the balance between the two major DSB repair pathways-nonhomologous end-joining and homologous recombination repair. Furthermore, PA28 gamma is found to be an ATM target, being recruited to the DNA damage sites and required for rapid accumulation of proteasomes at these sites. Our data reveal a novel ATM-PA28 gamma-proteasome axis of the DDR that is required for timely coordination of DSB repair.
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