生物
基因组不稳定性
DNA修复
基因组编辑
细胞生物学
癌症研究
DNA损伤
遗传学
DNA
基因组
基因
作者
Ondrej Beláň,Marie Sebald,Marek Adamowicz,Roopesh Anand,Aleksandra Vančevska,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 Rueda,Simon J. Boulton
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-12-01
卷期号:82 (24): 4664-4680.e9
被引量:31
标识
DOI:10.1016/j.molcel.2022.11.008
摘要
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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