DDX11 loss causes replication stress and pharmacologically exploitable DNA repair defects
Nanda Kumar Jegadesan, Dana Branzei
Abstract
Significance Replication stress can affect development and is a hallmark of cancers. Warsaw breakage syndrome is a developmental disorder caused by mutations in the conserved DDX11 DNA helicase. Here, using human cellular models of DDX11 deficiency, we report that DDX11 helicase prevents replication stress and mediates homology-directed repair via homologous recombination. Mechanistically, DDX11 promotes resection, enabling RPA and RAD51 focus formation, and acts nonredundantly with the RAD51 mediators BRCA1 and BRCA2. As a result, targeting DDX11 confers improved chemotherapy responsiveness in both chemotherapy-sensitive and drug-resistant BRCA1/2-mutated cancers that regained homologous recombination proficiency by suppressor mutation or somatic reversion. The results pinpoint DDX11 as a critical replication stress mitigating factor whose targeting can improve chemotherapeutic response in a range of cancers.