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2015 ; 58
(5
): 767-79
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An Inhibitor of PIDDosome Formation
#MMPMID25936804
Thompson R
; Shah RB
; Liu PH
; Gupta YK
; Ando K
; Aggarwal AK
; Sidi S
Mol Cell
2015[Jun]; 58
(5
): 767-79
PMID25936804
show ga
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.
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