POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells

Mol Cell. 2022 Dec 15;82(24):4664-4680.e9. doi: 10.1016/j.molcel.2022.11.008. Epub 2022 Nov 30.


POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and is overexpressed in many cancers. POLQ inhibitors confer synthetic lethality in HR and Shieldin-deficient cancer cells, which has been proposed to reflect a critical dependence on the DSB repair pathway by MMEJ. Whether POLQ also operates independent of MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between POLQ helicase and polymerase activities promotes RPA displacement and ssDNA-gap fill-in, respectively. POLQ is also capable of microhomology-mediated gap skipping (MMGS), which generates deletions during gap repair that resemble the genomic scars prevalent in POLQ overexpressing cancers. Our findings implicate POLQ in mutagenic post-replicative gap sealing, which could drive genome evolution in cancer and whose loss places a critical dependency on HR for gap protection and repair and cellular viability.

Keywords: BRCA; BRCA genes; PARP; PARP inhibitors; POLQ; homologous recombination; post-replicative gap repair; replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair
  • DNA Replication / genetics
  • DNA, Single-Stranded / genetics
  • Genomic Instability
  • Humans
  • Neoplasms* / genetics
  • Synthetic Lethal Mutations


  • DNA, Single-Stranded