Abstract IA09: Replication fork stability confers chemoresistance in BRCA-deficient cells

Abstract

Abstract Brca1- and Brca2-deficient cells have reduced capacity to repair DNA double strand breaks (DSBs) by homologous recombination (HR) and consequently are hypersensitive to DNA damaging agents including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein PTIP protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore HR activity at DSBs. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn, protects nascent DNA strands from extensive degradation. More generally, acquisition of PARPi and cisplatin resistance is associated with replication fork (RF) protection in Brca2-deficient tumor cells that do not develop Brca2-reversion mutations. Disruption of multiple proteins including PARP1 and CHD4 leads to the same end point of RF protection, highlighting the complexities by which tumor cells evade chemotherapeutic interventions and acquire drug resistance. Citation Format: Arnab Ray Chaudhuri, Elsa Callen, Xia Ding, Ewa Gogola, Alexandra A. Duarte, Ji-Eun Lee, Nancy Wong, Vanessa Lafarga, Jennifer A. Calvo, Nicholas J. Panzarino, Sam John, Amanda Day, Anna Vidal Crespo, Binghui Shen, Linda M. Starnes, Julian R. de Ruiter, Jeremy A. Daniel, Panagiotis A. Konstantinopoulos, David Cortez, Sharon B. Cantor, Oscar Fernandez-Capetillo, Kai Ge, Jos Jonkers, Sven Rottenberg, Shyam K. Sharan, André Nussenzweig. Replication fork stability confers chemoresistance in BRCA-deficient cells [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA09.