1. Involvement of the nuclear proteasome activator PA28 gamma in the cellular response to DNA double-strand breaks
- Author
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Jeroen Essers, Mickey C.T. Hu, Yael Ziv, Yaniv Lerenthal, Anthony J. Davis, Roland Kanaar, Yosef Shiloh, Adva Levy-Barda, Nicole van Vliet, Zhengping Shao, Young Min Chung, David J. Chen, Surgery, and Molecular Genetics
- Subjects
Proteasome Endopeptidase Complex ,DNA Repair ,DNA damage ,DNA repair ,Immunoblotting ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Protein Serine-Threonine Kinases ,DNA-binding protein ,Autoantigens ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Report ,Humans ,Immunoprecipitation ,DNA Breaks, Double-Stranded ,RNA, Small Interfering ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Activator (genetics) ,Tumor Suppressor Proteins ,Cell Biology ,DNA repair protein XRCC4 ,Flow Cytometry ,Molecular biology ,Cell biology ,DNA-Binding Proteins ,chemistry ,Proteasome ,030220 oncology & carcinogenesis ,RNA Interference ,DNA ,Developmental Biology ,Signal Transduction - Abstract
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.
- Published
- 2011