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Proteostasis is essential for maintaining the proper function of the proteome and diverse cellular processes. The ubiquitin system plays a central role in proteostasis by regulating protein stability, trafficking, and termination. Under cellular stress, rapid proteome remodeling is required to maintain proteostasis and support adaptive cellular stress-response pathways, including the DNA damage response (DDR). Proper DDR function relies on precise control of protein abundance and signaling dynamics, primarily achieved through ubiquitin-mediated proteostatic regulation involving both proteolytic degradation and non-proteolytic scaffolding function. Dysregulation of the ubiquitin system alters the dynamic control of the DDR cascade, leading to genomic instability and disease progression. Therefore, targeting key components of the ubiquitin system may restore proper DDR signaling regulation and offer novel therapeutic opportunities for disease treatment. In this review, we summarize the role of the ubiquitin system in proteostasis-mediated DDR regulation and explore the potential of targeting ubiquitin system components as therapeutic strategies in cancer treatment.