DNA polymerase theta helicase domain (POLQ-hel)

The DNA polymerase theta helicase domain (sometimes referred to as Polθ-hel) is the N-terminal domain of DNA polymerase theta (POLQ), a unique mammalian enzyme essential for DNA repair via microhomology-mediated end joining (MMEJ). The helicase domain has relatively weak 3′–5′-direction ATP-dependent DNA unwinding activity and strong ATP-independent single-stranded DNA annealing, and it is structurally distinct from other SF2 family helicases. It efficiently dissociates single-stranded DNA-binding proteins (e.g., the RPA complex), thereby facilitating the bridging and joining of broken DNA ends required for MMEJ. The helicase domain can form dimers or tetramers, likely aiding the alignment of broken DNA for repair. Due to its role in cancer cell survival (particularly in tumors with defective homologous recombination, such as BRCA-mutant cancers), the Polθ helicase has emerged as a promising drug target. The small-molecule inhibitor AB25583 specifically binds the helicase channel, inhibits its ATPase activity, and selectively kills BRCA-deficient cells, underscoring the clinical potential of targeting this domain for precision oncology.

Other names

Polθ helicasePOLQ-helDNA polymerase theta helicaseDNA polymerase theta HLD (helicase-like domain)POLQ helicase domain

Inhibition of ATPase and DNA unwinding/annealing activities, Allosteric modulation of the helicase conformational state