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, Lihua J. Zhu, Neil Johnson, Sharon B. Cantor

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). 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 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 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, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs 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. Significance: This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease.

Original languageEnglish
Pages (from-to)1388-1397
Number of pages10
JournalCancer research
Volume81
Issue number5
DOIs
StatePublished - Mar 1 2021

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