DC7
Synergy between HPF1-mediated serine ADP-ribosylation of chromatin and ALC1 chromatin remodeller function in the DNA damage mediated and NAD-dependent activation of the nuclear enzymes PARP1/2.
Background: The conversion of the metabolite NAD into poly-(ADP-ribose) (PAR) during DNA damage is crucial in cancer. PARP1/2 inhibitors are clinically useful but have toxicity and resistance issues. HPF1 completely alters PARylation's target amino acid in the DNA damage response, yet its potential as a cancer target remains underexplored
Objectives: (1) Dissect the functions and biological roles of ALC1 and HPF1 in PARP1/2-mediated DNA damage responses; (2) Determine the role of HPF1 in the NAD-dependent and poly-(ADP-ribose)-mediated recruitment of ALC1 chromatin remodeller to DNA damage sites; (3) Establish the mechanism of PARP inhibitor sensitization mediated by ALC1 and HPF1 in isolation and together.