DNA damage is a double-edged sword in cancer cells. On the one hand, DNA damage exacerbates gene mutation frequency and cancer risk. Mutations in key DNA repair genes, such as breast cancer 1 (BRCA1) and/or breast cancer 2 (BRCA2), induce genomic instability and promote tumorigenesis. On the other hand, the induction of DNA damage using chemical reagents or radiation kills cancer cells effectively. Cancer-burdening mutations in key DNA repair-related genes imply relatively high sensitivity to chemotherapy or radiotherapy because of reduced DNA repair efficiency. Therefore, designing specific inhibitors targeting key enzymes in the DNA repair pathway is an effective way to induce synthetic lethality with chemotherapy or radiotherapy in cancer therapeutics. This study reviews the general pathways involved in DNA repair in cancer cells and the potential proteins that could be targeted for cancer therapeutics.

DNA double-strand breaks (DSBs) are the most lethal DNA damages which lead to severe genome instability. Phosphorylation is one of the most important protein post-translation modifications involved in DSBs repair regulation. Kinases and phosphatases play coordinating roles in DSB repair by phosphorylating and dephosphorylating various proteins. Recent research has shed light on the importance of maintaining a balance between kinase and phosphatase activities in DSB repair. The interplay between kinases and phosphatases plays an important role in regulating DNA-repair processes, and alterations in their activity can lead to genomic instability and disease. Therefore, study on the function of kinases and phosphatases in DSBs repair is essential for understanding their roles in cancer development and therapeutics. In this review, we summarize the current knowledge of kinases and phosphatases in DSBs repair regulation and highlight the advancements in the development of cancer therapies targeting kinases or phosphatases in DSBs repair pathways. In conclusion, understanding the balance of kinase and phosphatase activities in DSBs repair provides opportunities for the development of novel cancer therapeutics.

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.