Venerdì 5 aprile appuntamento con il ciclo di Seminari del DSF: "PARP inhibitor sensitization by deregulated PARP1 turnover".
L'incontro si svolgerà dalle 13:00 alle 13:40 in aula seminari al II piano di l.go Donegani 2 (ex Wild).
Il talk sarà tenuto da Marco Gatti (Università di Zurigo).
Poly(ADP-ribose) polymerase 1 (PARP1, ARTD1) has multiple important roles in metabolism, stress signaling, chromatin dynamics, transcription and DNA repair, and it is the target of PARP inhibitors (PARPi) used as therapy for BRCA-mutated ovarian and breast tumors. The cytotoxicity of PARPi is in part caused by the ability of PARPi to lock PARP1 in an inactive conformation and thereby stabilize potentially toxic PARP1-DNA complexes, a mechanism that is referred to as PARP trapping. A hypothesis based on the PARP trapping model is that PARPi might work best in cancer cells expressing high levels of PARP1, with consequentially increased cytotoxic PARP1 trapping. PARP1 is indeed upregulated in various cancers and PARP1 expression may have prognostic value for PARPi-based cancer treatment. A relatively novel and still insufficiently explored aspect of PARP biology is the interplay between PARylation and ubiquitin-dependent protein turnover. In order to identify components of the ubiquitin-proteasome machinery with hitherto uncharacterized roles in the regulation of PARP1 steady-state levels, we employed a targeted siRNA approach in conjunction with high-throughput single cell imaging and found that posttranslational regulation of PARP1 turnover indeed impacts cellular sensitivity to PARPi. Our current work is aimed at dissecting the molecular details of ubiquitin-dependent PARP1 turnover and to study its implications for PARPi responses, both in BRCA-deficient and in BRCA-proficient settings.