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

Marie-France Langelier, Ramya Billur, Aleksandr Sverzhinsky, Ben E. Black and John M. Pascal ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27043-8

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