3.1. PA28γ in DNA damage response

DNA double-strand breaks (DSBs) may lead to chromosomal rearrangements, dysfunctional gene expression, or even aneuploidy, if not properly being targeted by the DNA damage response (DDR). The DDR is a tightly regulated nuclear process, organized majorly by posttranslational modification (PTM) signals, implemented by certain stress protein kinases. It has been presumed that DSB mobility and nuclear chromatin dynamics may serve to support DNA repair in nuclear sub-compartments [67]. Major DNA repair pathways are carried out within a highly organized three-dimensional nuclear environment. Homologous recombination (HR) occurs throughout the cell cycle, while nonhomologous end joining (NHEJ) is restricted to S and G2 phases.

Recently, ATM- and PA28γ-dependent recruitment of 20S proteasomes to sites of DSB has been demonstrated by live cell imaging [42]. PA28γ depletion enhanced the focal retention of proteins of the DNA repair machinery (MDC1, 53BP1, RNF8, or BRCA1) at DNA damage sites, whereas early accumulation of focal proteins and initial formation of modified histone γH2AX were not affected. PA28γ silencing moderately reduced the NHEJ pathway, whereas the HR pathway was markedly enhanced. PA28γ seems to assemble proteasomes at the sites of DSB during early stages of the DNA repair pathway [42].
