Abstract
The emergence of precision medicine from the development of Poly (ADP-ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti-cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase-polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology-mediated end-joining (MMEJ) and translesion synthesis (TLS) have been discovered. Here, we provide a short review of Polθ‘s DNA repair activities and its potential as a drug target and highlight a recent report that reveals Polθ as a naturally occurring reverse transcriptase (RT) in mammalian cells.
Highlights
Molecular and Computational Biology, USC Dornsife Department of Biological Sciences, Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Since BRCA deficient cancer cells are impaired in homologous recombination (HR), they are highly susceptible to DNA damage compared to normal cells [4,5]
polymerase θ (Polθ) is upregulated in the majority (70%) of breast tumors and epithelial ovarian cancers [14,15,16,17,18], and its overexpression correlates with HR defects and a poor clinical outcome [14,15,16,19]
Summary
Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 are strongly predisposed to breast and ovarian cancer [1,2,3,4,5,6]. Since BRCA deficient cancer cells are impaired in HR, they are highly susceptible to DNA damage compared to normal cells [4,5]. Drugs that cause DNA damage or inhibit DNA repair, such as Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors, can cause synthetic lethality in BRCA deficient cells while sparing normal cells [4,7,8,9]. It remains important to identify and develop alternative drug targets involved in DNA repair for BRCA deficient cancers that reduce drug resistance and potential side effects. Studies performed in 2015 identified the multi-functional DNA repair protein DNA polymerase θ (Polθ) as a promising drug target in HR-deficient cancers [13,14].
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