DNA polymerase theta (POLQ) helicase domain (POLQ)

DNA polymerase theta (POLQ) is a multifunctional enzyme containing an N-terminal helicase domain and a C-terminal polymerase domain, primarily responsible for the microhomology-mediated end joining (MMEJ) DNA repair pathway [1]. It serves as a critical survival factor for cancer cells with defects in homologous recombination (HR), such as those harboring BRCA1 or BRCA2 mutations, making it a prime candidate for synthetic lethal therapeutic strategies [2]. The helicase domain of POLQ utilizes its ATPase activity to unwind double-stranded DNA and facilitate the annealing of microhomologous sequences during repair [1, 4]. Small molecule inhibitors targeting this specific domain, such as ART4215, are designed to disrupt MMEJ, leading to the accumulation of lethal DNA double-strand breaks in HR-deficient tumors [3]. Because POLQ expression is largely restricted to cancer cells and is nearly absent in healthy tissues, targeting its helicase domain offers a promising therapeutic window with potentially fewer side effects than traditional chemotherapy [2, 3]. Current clinical development focuses on using these inhibitors as monotherapy or in combination with PARP inhibitors to overcome or prevent drug resistance in various solid tumors [3].

Other names

DNA polymerase thetaPol thetaPOLQPolymerase (DNA directed) thetaPRO0327

Inhibition of the ATPase/helicase activity of POLQ to block microhomology-mediated end joining (MMEJ), inducing synthetic lethality in homologous recombination (HR)-deficient cells [2, 3].