An Inhibitor of PIDDosome Formation.
The PIDDosome-PIDD-RAIDD-caspase-2 complex-is a proapoptotic caspase-activation platform of elusive significance. DNA damage can initiate complex assembly via ATM phosphorylation of the PIDD death domain (DD), which enables RAIDD recruitment to PIDD. In contrast, the mechanisms limiting PIDDosome formation have remained unclear. We identify the mitotic checkpoint factor BubR1 as a direct PIDDosome inhibitor, acting in a noncanonical role independent of Mad2. Following its phosphorylation by ATM at DNA breaks, "primed" PIDD relocates to kinetochores via a direct interaction with BubR1. BubR1 binds the PIDD DD, competes with RAIDD recruitment, and negates PIDDosome-mediated apoptosis after ionizing radiation. The PIDDosome thus sequentially integrates DNA damage and mitotic checkpoint signals to decide cell fate in response to genotoxic stress. We further show that by sequestering PIDD at the kinetochore, BubR1 acts to delay PIDDosome formation until the next cycle, defining a new mechanism by which cells evade apoptosis during mitosis.
Department of Medicine, Division of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ruth
R
Thompson
Department of Medicine, Division of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Richa B
RB
Shah
Department of Medicine, Division of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Peter H
PH
Liu
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Yogesh K
YK
Gupta
Department of Medicine, Division of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Kiyohiro
K
Ando
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Aneel K
AK
Aggarwal
Department of Medicine, Division of Hematology/Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: samuel.sidi@mssm.edu.
Samuel
S
Sidi
D000818:Animals; D053143:Caspase 2 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000201:enzymology; D064246:Mad2 Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction
D053418:Death Domain Receptor Signaling Adaptor Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C485896:PIDD1 protein, human; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases