Meta-Biol

• Pathways

DNA polymerase theta (POLQ) extends annealed microhomologous 3'-ssDNA overhangs at DNA double strand breaks (DSBs), using opposing overhangs as templates. POLQ can perform strand displacement synthesis, extending the overhangs beyond ssDNA-dsDNA junction point, which leads to the formation of displaced strand flaps (Kent et al. 2015). PARP1 (or possibly PARP2) is necessary for the recruitment of POLQ to DNA DSBs. POLQ-mediated DNA synthesis during microhomology mediated end joining (MMEJ) (also known as alternative nonhomologous end joining or alt-NHEJ or theta-mediated end joining - TMEJ) counteracts homologous recombination repair (HRR) and promotes survival of cells with a compromised HR pathway (Mateos-Gomez et al. 2015). POLQ is error-prone and introduces single nucleotide substitutions during DNA synthesis. HRR-deficient epithelial ovarian cancers frequently overexpress POLQ, which correlates with an increased frequency of somatic point mutations in these tumors (Ceccaldi et al. 2015).

BRCA2 regulates DSB repair pathway choice independent of RAD51 (Han et al. 2017) by inhibiting DNA polymerase theta-mediated end-joining (TMEJ) during the S and G2 phases of the cell cycle until M phase (Llorens-Agost et al. 2021). In BRCA2-deficient cells, TMEJ is inhibited by RAD52. Loss of RAD52 in BRCA2-deficient cells, leads to inappropriate DSB repair by TMEJ and cell death providing a rationale for the synthetic lethality of BRCA2 and RAD52 deficiencies (Llorens-Agost et al. 2021).