Protein degradation in DNA damage response

DNA damage is a major threat to genome integrity. To reduce its deleterious effects, cells have developed coordinated responses, collectively referred to as the “DNA damage response” pathway (DDR). In multicellular organisms, the DDR pathway has a critical role in preventing tumorigenesis, which accounts for the wide use of drugs targeting DDR factors in anti-cancer therapy. Post-translational modifications such as phosphorylation, ubiquitylation, acetylation, sumoylation are integral part of the DDR pathway. Ubiquitylation of DDR-related factors has recently emerged both as a switch initiating signaling cascades and as a proteolytic signal coordinating recruitment and disassembly of those proteins. In this review we will present evidence supporting an increasingly important role for the ubiquitin-proteasome-mediated degradation in regulating DDR at different levels.

► Both proteolytic and non-proteolytic functions of the UPS participate in DDR. ► Proteasome-dependent protein degradation regulates DDR at different stages. ► Proteasomal degradation participates in both activation and turn-off of the DDR.