title: Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks.
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 PA28γ (REGγ; PSME3) as a novel DDR player. PA28γ depletion leads to cellular radiomimetic sensitivity and a marked delay in DSB repair. Specifically, PA28γ deficiency abrogates the balance between the two major DSB repair pathways--nonhomologous end-joining and homologous recombination repair. Furthermore, PA28γ 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-PA28γ-proteasome axis of the DDR that is required for timely coordination of DSB repair.
authors: The David and Inez Myers Laboratory for Cancer Genetics, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Adva
authors: A
authors: Levy-Barda
authors: Yaniv
authors: Y
authors: Lerenthal
authors: Anthony J
authors: AJ
authors: Davis
authors: Young Min
authors: YM
authors: Chung
authors: Jeroen
authors: J
authors: Essers
authors: Zhengping
authors: Z
authors: Shao
authors: Nicole
authors: N
authors: van Vliet
authors: David J
authors: DJ
authors: Chen
authors: Mickey C-T
authors: MC
authors: Hu
authors: Roland
authors: R
authors: Kanaar
authors: Yael
authors: Y
authors: Ziv
authors: Yosef
authors: Y
authors: Shiloh
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001324:Autoantigens / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C099558:Ki antigen; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex