Dual function of HPF1 in the modulation of PARP1 and PARP2 activities

Poly(ADP-ribosyl)ation catalyzed by poly(ADP-ribose) polymerases (PARPs) is one of the immediate cellular responses to DNA damage. The histone PARylation factor 1 (HPF1) discovered recently to form a joint active site with PARP1 and PARP2 was shown to limit the PARylation activity of PARPs and stimulate their NAD+-hydrolase activity. Here we demonstrate that HPF1 can stimulate the DNA-dependent and DNA-independent autoPARylation of PARP1 and PARP2 as well as the heteroPARylation of histones in the complex with nucleosome. The stimulatory action is detected in a defined range of HPF1 and NAD+ concentrations at which no HPF1-dependent enhancement in the hydrolytic NAD+ consumption occurs. PARP2, comparing with PARP1, is more efficiently stimulated by HPF1 in the autoPARylation reaction and is more active in the heteroPARylation of histones than in the automodification, suggesting a specific role of PARP2 in the ADP-ribosylation-dependent modulation of chromatin structure. Possible role of the dual function of HPF1 in the maintaining PARP activity is discussed. Kurgina et al. conduct in vitro characterization of the effect of HPF1 on the catalytic output of PARP1 and PARP2 under several experimental conditions. The authors report that the DNAdependent and DNA-independent autoPARylation of PARP1 and PARP2, as well as the heteroPARylation of histones in complex with the nucleosome are stimulated by HPF1 in a certain range of HPF1 and NAD + concentrations.