Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks

Adva Levy-Barda, Yaniv Lerenthal, Anthony J. Davis, Young Min Chung, Jeroen Essers, Zhengping Shao, Nicole Van Vliet, David J. Chen, Mickey C T Hu, Roland Kanaar, Yael Ziv, Yosef Shiloh

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4300-4310
Number of pages11
JournalCell Cycle
Volume10
Issue number24
DOIs
StatePublished - Dec 15 2011

Keywords

  • ATM
  • DNA repair
  • Double-strand breaks
  • Genomic stability
  • PA28γ (PSME3)
  • Proteasome

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks'. Together they form a unique fingerprint.

  • Cite this

    Levy-Barda, A., Lerenthal, Y., Davis, A. J., Chung, Y. M., Essers, J., Shao, Z., Van Vliet, N., Chen, D. J., Hu, M. C. T., Kanaar, R., Ziv, Y., & Shiloh, Y. (2011). Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks. Cell Cycle, 10(24), 4300-4310. https://doi.org/10.4161/cc.10.24.18642