Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.

Ewa Gogola, Alexandra A Duarte, Julian R De Ruiter, Wouter W Wiegant, Jonas A Schmid, Roebi De Bruijn, Dominic I James, Sergi Guerrero Llobet, Daniel J Vis, Stefano Annunziato, Bram Van Den Broek, Marco Barazas, Ariena Kersbergen, Marieke Van De Ven, Madalena Tarsounas, Donald J Ogilvie, Marcel Van Vugt, Lodewyk F A Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico Van Attikum, Piet Borst … & Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major...
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