AI Article Synopsis
- POLQ is an important protein for repairing DNA double-strand breaks (DSBs) through a process called microhomology-mediated end-joining (MMEJ) and is found at higher levels in various cancers.
- Inhibiting POLQ leads to synthetic lethality in cancer cells that lack certain repair mechanisms (like HR and Shieldin), suggesting a strong reliance on MMEJ for repair.
- The study reveals that when POLQ is absent, cells accumulate gaps in their DNA, and POLQ works in a way that could drive genetic changes in cancer, highlighting its role in both gap sealing and overall cell survival.
Article Abstract
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.
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| http://dx.doi.org/10.1016/j.molcel.2022.11.008 | DOI Listing |
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