Replication Gaps Underlie BRCA-deficiency and Therapy Response

Nicholas J. Panzarino, John J. Krais, Ke Cong, Min Peng, Michelle Mosqueda, Sumeet U. Nayak, Samuel M. Bond, Jennifer A. Calvo, Mihir B. Doshi, Matt Bere, Jianhong Ou, Bin Deng (+3 others)
2020 Cancer Research  
Challenging this assumption are recent findings that indicate chemotherapies such as cisplatin used to treat BRCA-deficient tumors do not initially cause DNA double-strand-breaks (DSB). Here we show that single-stranded DNA (ssDNA) replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to
more » ... ed in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSB were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSB are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose they are fundamental to the mechanism-of-action of genotoxic chemotherapies.
doi:10.1158/0008-5472.can-20-1602 pmid:33184108 fatcat:sjvzish3wzdxfah5yxb4ijt3gy