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

• DOI: 10.1016/j.molcel.2022.11.008
• Publication Date: 2022-11-30T15:32:15Z
• Authors: Ondrej Belan; Marie Sebald; Marek Adamowicz; Roopesh Anand; Aleksandra Vancevska; Joana Neves; Vera Grinkevich; Graeme Hewitt; Sandra Segura-Bayona; Roberto Bellelli; Helen M.R. Robinson; Geoff S. Higgins; Graeme C.M. Smith; Stephen C. West; David S. Rueda; Simon J. Boulton
• Keywords: DNA Replication; Model organisms; 0301 basic medicine; 0303 health sciences; DNA End-Joining Repair; Genome Integrity & Repair; DNA, Single-Stranded; Cell Biology; Biochemistry & Proteomics; Genomic Instability; 3. Good health; 03 medical and health sciences; Neoplasms; Humans; Cell Cycle & Chromosomes; DNA Breaks, Double-Stranded; Synthetic Lethal Mutations; Genetics & Genomics; Structural Biology & Biophysics

POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and overexpressed in many cancers. inhibitors confer synthetic lethality HR Shieldin-deficient cancer cells, which has been proposed to reflect critical dependence on the pathway MMEJ. Whether also operates independent 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 helicase polymerase activities promotes RPA displacement ssDNA-gap fill-in, respectively. capable gap skipping (MMGS), generates deletions during resemble genomic scars prevalent overexpressing Our findings implicate mutagenic sealing, could drive genome evolution whose places dependency for protection cellular viability.