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HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications

Author

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  • Marie-France Langelier

    (Université de Montréal)

  • Ramya Billur

    (University of Pennsylvania)

  • Aleksandr Sverzhinsky

    (Université de Montréal)

  • Ben E. Black

    (University of Pennsylvania)

  • John M. Pascal

    (Université de Montréal)

Abstract

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27043-8
    DOI: 10.1038/s41467-021-27043-8
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