Thompson Ruth, Shah Richa B, Liu Peter H, Gupta Yogesh K, Ando Kiyohiro, Aggarwal Aneel K, Sidi Samuel
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 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.
Mol Cell. 2015 Jun 4;58(5):767-79. doi: 10.1016/j.molcel.2015.03.034. Epub 2015 Apr 30.
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.
PIDDosome-PIDD-RAIDD-半胱天冬酶-2复合物是一个具有难以捉摸的重要性的促凋亡半胱天冬酶激活平台。DNA损伤可通过PIDD死亡结构域（DD）的ATM磷酸化启动复合物组装，这使得RAIDD能够被招募到PIDD。相比之下，限制PIDDosome形成的机制仍不清楚。我们确定有丝分裂检查点因子BubR1是一种直接的PIDDosome抑制剂，以独立于Mad2的非经典作用发挥作用。在DNA断裂处被ATM磷酸化后，“引发的”PIDD通过与BubR1的直接相互作用重新定位于动粒。BubR1结合PIDD DD，与RAIDD招募竞争，并在电离辐射后消除PIDDosome介导的细胞凋亡。因此，PIDDosome依次整合DNA损伤和有丝分裂检查点信号，以决定细胞对基因毒性应激的命运。我们进一步表明，通过将PIDD隔离在动粒处，BubR1起到延迟PIDDosome形成直至下一个周期的作用，定义了一种细胞在有丝分裂期间逃避凋亡的新机制。
