Polymerase theta (Polθ) and cancer: Role in tumor progression and potential as a therapeutic target

Abstract

DNA double-strand breaks (DSBs) are a severe form of DNA damage that can lead to large chromosomal deletions, gene inactivation, genomic rearrangements, and cell death. Cellular repair pathways are vital for maintaining genomic stability and integrity, both of which are essential for cell growth and development. Recent studies highlight that DNA polymerase theta (Polθ) is a promising target in cancer research, as inhibiting Polθ is synthetically lethal in the context of homologous recombination (HR) deficiencies, such as mutations in the breast cancer susceptibility genes BRCA1 and BRCA2. Exploring the relationship between Polθ and cancer may offer new therapeutic strategies. This review outlines the mechanisms of DSB repair pathways, with a focus on the role of Polθ in polymerase theta-mediated end-joining (TMEJ). We also discuss the structure and biological functions of Polθ, emphasizing the synthetic lethal interactions between Polθ and various DNA repair genes in cancer therapy. Furthermore, we examine the types and therapeutic effects of Polθ inhibitors in tumor treatment, as well as their clinical applications and challenges. Although further research is required to resolve challenges in clinical applications, investigating Polθ inhibitors as targeted therapies could have implications for anticancer therapies, particularly in HR-deficient cancers.