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

Madalena Tarsounas, Stefano Annunziato, Dominic I James, Miguel Andújar-Sánchez, Sven Rottenberg, Sergi Guerrero Llobet, Ariena Kersbergen, Ewa Gogola, Alexandra A Duarte, Haico Van Attikum, Roebi De Bruijn, Jos Jonkers, Marco Barazas, Julian R De Ruiter, Piet Borst, Jiri Bartek, Daniel J Vis, Lodewyk F A Wessels, Bram Van Den Broek, Wouter W Wiegant, Marcel Van Vugt, Irina Gromova, Massimo Lopes, Jirina Bartkova, Jonas A Schmid … & Marieke Van De Ven
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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