Understanding single stranded DNA gaps: from formation to fate

Single-stranded DNA gaps (ssDNA gaps) have emerged as a potential indicator of therapeutic response in cancer. Accumulation of ssDNA gaps is associated with increased sensitivity of cancer cells to genotoxic therapies like PARP inhibitors (PARPi) and cisplatin chemotherapy. However, efficient repair or suppression of ssDNA gap formation is associated with therapy resistance and treatment failure. Therefore, understanding how ssDNA gaps form and are repaired can help identify biomarkers that can guide new treatment strategies to overcome resistance. In this review, we discuss different sources of ssDNA gap formation and the repair mechanisms that have been characterized to date. We bring together current knowledge on how these gaps are processed and what their ultimate fate may be. Finally, we discuss how established drugs like PARPi, hydroxyurea, and platinum compounds, induce and/or exploit ssDNA gaps. Throughout this review, we highlight ssDNA gaps as a potential therapeutic vulnerability that can be used to advance personalized cancer therapy.