Abstract
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.
Highlights
Poly(ADP-ribosyl)ation catalyzed by poly(ADP-ribose) polymerases (PARPs) is one of the immediate cellular responses to DNA damage
Influence of histone PARylation factor 1 (HPF1) on the activities of PARP1 and PARP2 in the automodification reaction and heteromodification of histones was tested at varied concentrations of HPF1
PARP1, PARP2, and histones determined by normalization of the ADP-ribose amounts covalently bound to the given protein in the presence of HPF1 to the respective amount in the absence of HPF1 or its minimal concentration. e, f Histograms show distribution (%) of the total amount of covalently bound [32P]ADP-ribose in each sample between the modified PARP1(PARP2) and histones
Summary
Poly(ADP-ribosyl)ation catalyzed by poly(ADP-ribose) polymerases (PARPs) is one of the immediate cellular responses to DNA damage. 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. It was proposed that HPF1 binds only the DNA-activated form of PARP1/PARP2 because the autoinhibitory helical domain (HD) when bound to the ADP-ribosyl transferase (ART) subdomain of the catalytic (CAT) domain prevents complex formation of HPF1 with PARP1/ PARP222,26–29. In addition to affecting the substrate specificity and the length of polymer chain in the ADP-ribosylation reaction, HPF1 was shown to enhance NAD+-hydrolysis catalyzed by PARP131. It was shown that initiation and elongation steps of ADP-ribosylation are distinctly regulated by HPF1, ARH3, and PARG hydrolases, and that the HPF1-dependent initial attachment of ADP-ribose to Ser residue can be elongated by PARP1 alone[32]. The comparative study of the mechanism of HPF1-dependent modulation of the activities of PARP1 and PARP2 is of particular interest
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