HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications.

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This "hit and run" mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

Langelier MF ，Billur R ，Sverzhinsky A ，Black BE ，Pascal JM ... -  《Nature Communications》

HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.

Suskiewicz MJ ，Zobel F ，Ogden TEH ，Fontana P ，Ariza A ，Yang JC ，Zhu K ，Bracken L ，Hawthorne WJ ，Ahel D ，Neuhaus D ，Ahel I ... -  《-》

[Poly(ADP-Ribose) Polymerases 1 and 2: Classical Functions and Interaction with New Histone Poly(ADP-Ribosyl)ation Factor HPF1].

Kurgina TA ，Lavrik OI 《-》

HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones.

Sun FH ，Zhao P ，Zhang N ，Kong LL ，Wong CCL ，Yun CH ... -  《Nature Communications》

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 TA ，Moor NA ，Kutuzov MM ，Naumenko KN ，Ukraintsev AA ，Lavrik OI ... -  《Communications Biology》