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

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent study by Suskiewicz et al. apply to Moreover, we quantitatively characterize the key residues necessary for binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit automodification, and facilitates HPF1/Pduanyu371 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting

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