2. Academic Validation
  3. PARP4 ADP-ribosylates PIDD1 to complete a phospho/SUMO/PAR-ylation cascade that orchestrates PIDDosome assembly

PARP4 ADP-ribosylates PIDD1 to complete a phospho/SUMO/PAR-ylation cascade that orchestrates PIDDosome assembly

  • Sci Adv. 2026 May;12(18):eadz9284. doi: 10.1126/sciadv.adz9284.
Richa B Shah 1 2,  Yuanyuan Li 1 2,  Ashley Person 3,  Léonie Frigon 4,  Nina Ðukić 5,  Ela Kini 1 2,  Raymond Chen 1 2,  John M Pascal 4,  Michael S Cohen 3,  Ivan Ahel 5,  John D Haley 6,  Samuel Sidi 1 2 7
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology and Medical Oncology, Mount Sinai Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Cell, Developmental and Regenerative Biology, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA.
  • 4 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada.
  • 5 Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
  • 6 Department of Pathology Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
  • 7 Department of Oncological Sciences, Mount Sinai Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 42054439 DOI: 10.1126/sciadv.adz9284
Abstract

Adenosine diphosphate (ADP) ribosylation (ADPr) regulates multiple stress responses, yet substrates in the apoptotic machinery remain elusive. We show that a single, DNA damage-induced ADPr event controls proapoptotic PIDDosome (PIDD1/RAIDD/caspase-2) formation in response to unresolved interstrand DNA cross-links (ICL). ADPr targets conserved E783 in the PIDD1 death domain (DD); is catalyzed by poly(ADP-ribose) polymerase 4 (PARP4), a phylogenetically orphan PARP of previously unknown function; is reversed by the ribosylhydrolase activity of PARP14; and is triggered by Ataxia Telangiectasia and RAD3-related (ATR) phosphorylation-induced, PIAS1-mediated SUMOylation of the PIDD1 DD, which enables PARP4 docking. PIDD1 ADPr is dispensable for the recruitments of RAIDD and caspase-2 but essential for the dimerization of the Caspase. Hence, denying E783 ADPr spares the onset of PIDDosome assembly but blocks its completion, thus eliminating caspase-2 activation and ensuing Apoptosis. Conversely, removal of PARP14 forces Apoptosis, even in cells with tolerable damage. The data identify PARP4 as an ICL response effector and illuminate a three-step modification sequence of the PIDD1 DD that conducts PIDDosome assembly from initiation to completion.

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