DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects.

Abstract

<i>DDX11</i> encodes an iron-sulfur cluster DNA helicase required for development, mutated, and overexpressed in cancers. Here, we show that loss of <i>DDX11</i> causes replication stress and sensitizes cancer cells to DNA damaging agents, including poly ADP ribose polymerase (PARP) inhibitors and platinum drugs. We find that DDX11 helicase activity prevents chemotherapy drug hypersensitivity and accumulation of DNA damage. Mechanistically, DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in manners nonredundant with BRCA1 and BRCA2. As a result, <i>DDX11</i> down-regulation aggravates the chemotherapeutic sensitivity of <i>BRCA1</i>/<i>2</i>-mutated cancers and resensitizes chemotherapy drug-resistant <i>BRCA1</i>/<i>2</i>-mutated cancer cells that regained homologous recombination proficiency. The results further indicate that DDX11 facilitates recombination repair by assisting double strand break resection and the loading of both RPA and RAD51 on single-stranded DNA substrates. We propose DDX11 as a potential target in cancers by creating pharmacologically exploitable DNA repair vulnerabilities.