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

Fa-Hui Sun, Peng Zhao, Nan Zhang, Lu-Lu Kong, Catherine C. L. Wong and Cai-Hong Yun ()
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Fa-Hui Sun: Peking University Health Science Center
Peng Zhao: Peking University Health Science Center
Nan Zhang: Peking University Health Science Center
Lu-Lu Kong: Peking University Health Science Center
Catherine C. L. Wong: Peking University Health Science Center
Cai-Hong Yun: Peking University Health Science Center

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) 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 HPF1/PARP1-CAT 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 HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 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 PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.

Date: 2021
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DOI: 10.1038/s41467-021-21302-4

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