The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome

Ivo A. Hendriks, Sara C. Buch-Larsen, Evgeniia Prokhorova, Jonas D. Elsborg, Alexandra K.L.F.S. Rebak, Kang Zhu, Dragana Ahel, Claudia Lukas, Ivan Ahel and Michael L. Nielsen ()
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Ivo A. Hendriks: University of Copenhagen
Sara C. Buch-Larsen: University of Copenhagen
Evgeniia Prokhorova: University of Oxford
Jonas D. Elsborg: University of Copenhagen
Alexandra K.L.F.S. Rebak: University of Copenhagen
Kang Zhu: University of Oxford
Dragana Ahel: University of Oxford
Claudia Lukas: University of Copenhagen
Ivan Ahel: University of Oxford
Michael L. Nielsen: University of Copenhagen

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Despite the involvement of Poly(ADP-ribose) polymerase-1 (PARP1) in many important biological pathways, the target residues of PARP1-mediated ADP-ribosylation remain ambiguous. To explicate the ADP-ribosylation regulome, we analyze human cells depleted for key regulators of PARP1 activity, histone PARylation factor 1 (HPF1) and ADP-ribosylhydrolase 3 (ARH3). Using quantitative proteomics, we characterize 1,596 ADP-ribosylation sites, displaying up to 1000-fold regulation across the investigated knockout cells. We find that HPF1 and ARH3 inversely and homogenously regulate the serine ADP-ribosylome on a proteome-wide scale with consistent adherence to lysine-serine-motifs, suggesting that targeting is independent of HPF1 and ARH3. Notably, we do not detect an HPF1-dependent target residue switch from serine to glutamate/aspartate under the investigated conditions. Our data support the notion that serine ADP-ribosylation mainly exists as mono-ADP-ribosylation in cells, and reveal a remarkable degree of histone co-modification with serine ADP-ribosylation and other post-translational modifications.

Date: 2021
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DOI: 10.1038/s41467-021-26172-4

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