Damaged DNA leads to genomic instability that causes many diseases such as cancer. Cells evolved the DNA damage response (DDR), which recognizes and efficiently repairs damaged DNA through the action of highly coordinated signalling mechanisms. Recently, a non-degradation-linked Lys(K)63-ubiquitin signal emerged as a signalling pathway essential for orchestration of the DDR after DNA double strand breaks (DSBs). How the ubiquitin-dependent proteasomal degradation system (UPS) coordinates DDR after DSBs is still poorly understood. Here, we review the evidence, suggesting the involvement of the degradation-linked K48-ubiquitin signal and the proteasome at the sites of DSBs. Based on this we propose the UPS as a central element in the orchestration of the DDR at the sites of DSBs. The suggested model is also discussed in the context of anti-cancer therapy.