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

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. Wh...

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Vydáno v:Molecular cell Ročník 82; číslo 24; s. 4664
Hlavní autoři: Belan, Ondrej, Sebald, Marie, Adamowicz, Marek, Anand, Roopesh, Vancevska, Aleksandra, Neves, Joana, Grinkevich, Vera, Hewitt, Graeme, Segura-Bayona, Sandra, Bellelli, Roberto, Robinson, Helen M R, Higgins, Geoff S, Smith, Graeme C M, West, Stephen C, Rueda, David S, Boulton, Simon J
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 15.12.2022
Témata:
DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA Replication - genetics
DNA, Single-Stranded - genetics
Genomic Instability
Humans
Neoplasms - genetics
Synthetic Lethal Mutations
BRCA
POLQ
post-replicative gap repair
replication stress
homologous recombination
PARP inhibitors
BRCA genes
PARP
ISSN:1097-4164, 1097-4164
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2022.11.008