Involvement of the nuclear proteasome activator PA28γ in the cellular response to DNA double-strand breaks
Cell Cycle , Volume 10 - Issue 24 p. 4300- 4310
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.
|ATM, DNA repair, Double-strand breaks, Genomic stability, PA28γ (PSME3), Proteasome|
|This work was funded by the European Commission 7th Framework Programme; grant id fp7/259893 - The DNA damage response and breast cancer (DDRESPONSE)|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Levy-Barda, A, Lerenthal, Y, Davis, A.J, Chung, Y, Essers, J, Shao, Z, … 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. doi:10.4161/cc.10.24.18642