POLQ encodes DNA polymerase theta, a low-fidelity polymerase with intrinsic helicase activity that mediates microhomology-mediated end-joining (MMEJ), an error-prone alternative pathway for double-strand break (DSB) repair 1. POLQ functions by binding resected DSB ends and facilitating base pairing of microhomologous sequences (2-6 bp) in overhangs, then extending strands using the opposing overhang as template 1. The polymerase's helicase activity promotes RPA complex dissociation from resected breaks, enabling annealing and subsequent joining while simultaneously preventing RAD51 accumulation and inhibiting homologous recombination 2. POLQ also seals post-replicative ssDNA gaps through microhomology-mediated gap skipping, generating deletions characteristic of POLQ-overexpressing cancers 2. Although error-prone and genomically destabilizing, MMEJ repairs persistent DSBs originating in S-phase during mitosis when canonical NHEJ and HR are less active 3. POLQ exhibits synthetic lethality with HR-deficiency (BRCA1/2 mutations), making it a therapeutic target in HR-deficient cancers including ovarian, pancreatic, and prostate adenocarcinomas 14. POLQ inhibition activates cGAS-STING immune signaling in HR-deficient tumors, enhancing CD8+ T-cell infiltration 4. POLQ-mediated MMEJ also mediates reversion mutations that drive acquired PARP inhibitor resistance, with 60% of frameshift-mediated reversions displaying microhomology flanks 5.