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

Author

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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)

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.

Suggested Citation

  • 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 & Michael L. Nielsen, 2021. "The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26172-4
    DOI: 10.1038/s41467-021-26172-4
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    1. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. 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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