2. Academic Validation
  3. Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure

Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure

  • Nat Commun. 2024 Oct 24;15(1):9195. doi: 10.1038/s41467-024-53412-0.
Richa B Shah 1 2,  Yuanyuan Li 1 2,  Honglin Yu 1 2,  Ela Kini 1 2,  Samuel Sidi 3 4 5
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.
  • 4 Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.
  • 5 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.
PMID: 39448602 DOI: 10.1038/s41467-024-53412-0
Abstract

SUMOylation regulates numerous cellular stress responses, yet targets in the apoptotic machinery remain elusive. We show that a single, DNA damage-induced monoSUMOylation event controls PIDDosome (PIDD1/RAIDD/caspase-2) formation and apoptotic death in response to unresolved DNA interstrand crosslinks (ICLs). SUMO-1 conjugation occurs on conserved K879 in the PIDD1 death domain (DD); is catalyzed by PIAS1 and countered by SENP3; and is triggered by ATR phosphorylation of neighboring T788 in the PIDD1 DD, which enables PIAS1 docking. Phospho/SUMO-PIDD1 proteins are captured by nucleolar RAIDD monomers via a SUMO-interacting motif (SIM) in the RAIDD DD, thus compartmentalizing nascent PIDDosomes for caspase-2 recruitment. Denying SUMOylation or the SUMO-SIM interaction spares the onset of PIDDosome assembly but blocks its completion, thus eliminating the apoptotic response to ICL repair failure. Conversely, removal of SENP3 forces Apoptosis, even in cells with tolerable ICL levels. SUMO-mediated PIDDosome control is also seen in response to DNA breaks but not supernumerary centrosomes. These results illuminate PIDDosome formation in space and time and identify a direct role for SUMOylation in the assembly of a major pro-apoptotic device.

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