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

Author

Listed:
  • Fa-Hui Sun

    (Peking University Health Science Center
    Peking University Health Science Center
    Peking University Health Science Center)

  • Peng Zhao

    (Peking University Health Science Center
    Peking University Health Science Center
    Peking University Health Science Center)

  • Nan Zhang

    (Peking University Health Science Center
    Peking University)

  • Lu-Lu Kong

    (Peking University Health Science Center
    Peking University Health Science Center
    Peking University Health Science Center)

  • Catherine C. L. Wong

    (Peking University Health Science Center)

  • Cai-Hong Yun

    (Peking University Health Science Center
    Peking University Health Science Center
    Peking University Health Science Center)

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.

Suggested Citation

  • Fa-Hui Sun & Peng Zhao & Nan Zhang & Lu-Lu Kong & Catherine C. L. Wong & Cai-Hong Yun, 2021. "HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21302-4
    DOI: 10.1038/s41467-021-21302-4
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    Cited by:

    1. Zita Fábián & Ellen S. Kakulidis & Ivo A. Hendriks & Ulrike Kühbacher & Nicolai B. Larsen & Marta Oliva-Santiago & Junhui Wang & Xueyuan Leng & A. Barbara Dirac-Svejstrup & Jesper Q. Svejstrup & Micha, 2024. "PARP1-dependent DNA-protein crosslink repair," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Luka Bacic & Guillaume Gaullier & Jugal Mohapatra & Guanzhong Mao & Klaus Brackmann & Mikhail Panfilov & Glen Liszczak & Anton Sabantsev & Sebastian Deindl, 2024. "Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Marie-France Langelier & Ramya Billur & Aleksandr Sverzhinsky & Ben E. Black & John M. Pascal, 2021. "HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Pietro Fontana & Sara C. Buch-Larsen & Osamu Suyari & Rebecca Smith & Marcin J. Suskiewicz & Kira Schützenhofer & Antonio Ariza & Johannes Gregor Matthias Rack & Michael L. Nielsen & Ivan Ahel, 2023. "Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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