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

  • Nat Commun. 2021 Feb 15;12(1):1028. doi: 10.1038/s41467-021-21302-4.
Fa-Hui Sun  #  1  2  3 ,  Peng Zhao  #  1  2  3 ,  Nan Zhang  4  5 ,  Lu-Lu Kong  1  2  3 ,  Catherine C L Wong  4 ,  Cai-Hong Yun  6  7  8
Affiliations
  • 1. Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing, China.
  • 2. Department of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, China.
  • 3. Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 4. School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 5. Center for Precision Medicine Multi-omics Research, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 6. Department of Biochemistry and Biophysics, Peking University Health Science Center, Beijing, China. [email protected].
  • 7. Department of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, China. [email protected].
  • 8. Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 33589610 DOI: 10.1038/s41467-021-21302-4
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.