Serine-linked PARP1 auto-modification controls PARP inhibitor response

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Documents

  • Evgeniia Prokhorova
  • Florian Zobel
  • Rebecca Smith
  • Siham Zentout
  • Ian Gibbs-Seymour
  • Kira Schützenhofer
  • Alessandra Peters
  • Joséphine Groslambert
  • Valentina Zorzini
  • Thomas Agnew
  • John Brognard
  • Nielsen, Michael Lund
  • Dragana Ahel
  • Sébastien Huet
  • Marcin J Suskiewicz
  • Ivan Ahel

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.

Original languageEnglish
Article number4055
JournalNature Communications
Volume12
Issue number1
Number of pages12
ISSN2041-1723
DOIs
Publication statusPublished - 2021

ID: 273584531