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

Abstract Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors initiate repair. Serine is the major residue for ADP-ribosylation upon damage, which strictly depends on HPF1. Here, we report crystal structures of human HPF1/PARP1-CAT ?HD complex at 1.98 Å resolution, mouse HPF1 1.71 1.57 respectively. Our mutagenesis data confirm that structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply PARP1. Moreover, quantitatively characterize key residues necessary HPF1/PARP1 binding. show through salt-bridging Glu284/Asp286, Arg239 positions Glu284 catalyze serine ADP-ribosylation, maintains local conformation limit PARP1 automodification, facilitates neutralizing negative charge Glu284. These findings, along with high-resolution data, may facilitate drug discovery targeting