DNA repair is an indispensable part of a cell's defence system against the devastating effects of DNA-damaging conditions. The regulation of this function is a really demanding situation, particularly when the stressing factors persist for a long time. In such cases, the depletion of existing DNA repair proteins has to be compensated by the induction of the analogous gene products. In addition, the arrest of transcription, which is another result of many DNA-damaging agents, needs to be overcome through regulation of transcription-specific DNA repair pathways. The involvement of the ubiquitin-proteasome system (UPS) in cancer- and chemotherapy-related DNA-damage repair relevant to the above transcriptional modification mechanisms are illustrated in this review. Furthermore, the contribution of UPS to the regulation of localization and accessibility of DNA repair proteins to chromatin, in response to cellular stress is discussed.