Serine-linked PARP1 auto-modification controls PARP inhibitor response

Evgeniia Prokhorova, Florian Zobel, Rebecca Smith, Siham Zentout, Ian Gibbs-Seymour, Kira Schützenhofer, Alessandra Peters, Joséphine Groslambert, Valentina Zorzini, Thomas Agnew, John Brognard, Michael L. Nielsen, Dragana Ahel, Sébastien Huet, Marcin J. Suskiewicz () and Ivan Ahel ()
Additional contact information
Evgeniia Prokhorova: Sir William Dunn School of Pathology, University of Oxford
Florian Zobel: Sir William Dunn School of Pathology, University of Oxford
Rebecca Smith: Univ Rennes, CNRS, Structure Fédérative de Recherche Biosit, IGDR (Institut de Génétique et Développement de Rennes) – UMR 6290
Siham Zentout: Univ Rennes, CNRS, Structure Fédérative de Recherche Biosit, IGDR (Institut de Génétique et Développement de Rennes) – UMR 6290
Ian Gibbs-Seymour: Sir William Dunn School of Pathology, University of Oxford
Kira Schützenhofer: Sir William Dunn School of Pathology, University of Oxford
Alessandra Peters: Sir William Dunn School of Pathology, University of Oxford
Joséphine Groslambert: Sir William Dunn School of Pathology, University of Oxford
Valentina Zorzini: Sir William Dunn School of Pathology, University of Oxford
Thomas Agnew: Sir William Dunn School of Pathology, University of Oxford
John Brognard: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute
Michael L. Nielsen: Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Dragana Ahel: Sir William Dunn School of Pathology, University of Oxford
Sébastien Huet: Univ Rennes, CNRS, Structure Fédérative de Recherche Biosit, IGDR (Institut de Génétique et Développement de Rennes) – UMR 6290
Marcin J. Suskiewicz: Sir William Dunn School of Pathology, University of Oxford
Ivan Ahel: Sir William Dunn School of Pathology, University of Oxford

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

Abstract: Abstract Poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.

Date: 2021
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DOI: 10.1038/s41467-021-24361-9

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