Abstract
We uncover a novel non-canonical function of ATR kinase in the control of PIDDosome activation, and show that under normal cellular conditions involving no replication stress, ATR kinase controls the phosphorylation of cellular NPM via pChk1 as well as the two phosphatases, PPM1D and PP1β. We show that pNPM triggers the dissociation of NPM from PIDD, preventing the cell from undergoing caspase 2 mediated cell death via PIDDosome, thereby acting as an endogenous negative regulator of PIDDosome activation. pChk1 interaction with NPM is abrogated following ATR kinase inhibition, leading to the drop in nucleoplasmic/chromatin pNPM level, inducing PIDD. Consistent with this mechanism, the phosphomimic mutants of Chk1 and NPM become refractory to ATR/pChk1 kinase inhibition by avoiding PIDDosome signalling.
Highlights
ATR kinase is studied largely in the context of externally imposed genotoxic stress, even though its endogenous basal level plays important homeostatic cellular functions
These assays revealed that prolonged ATR kinase inhibition (ATRi) causes cell death, which was specific to ATR inhibited cells (ATRi) but not to either ATM kinase inhibition (ATMi) or DNAPKc inhibition (DNAPKci)
The PP1β nuclear intensity dropped as a function of ATR inhibition time-course by 5h ATRi (Fig 6c-d). All these results put together suggest that ATR kinase actively maintains pNPM levels in the cells via Chk1 axis. We integrate these results into a model where we suggest that ATR kinase maintains the cellular pool of pChk1 and regulates the spatial localisation of PPM1D and PP1β phosphatase, which in turn leads to the build-up of sufficient level of pNPM in normal cells such that the normal cells are actively protected from NPM mediated activation of PIDDosome and caspase-2 functions, thereby preventing the cells from “tipping” into cell death
Summary
ATR kinase is studied largely in the context of externally imposed genotoxic stress, even though its endogenous basal level plays important homeostatic cellular functions. The known physiological function of ATR mainly focuses on its role as a DNA damage response kinase, largely in the context of externally imposed genotoxic or replication stress conditions [1,2]. The endogenous role of ATR kinase in the absence of imposed genotoxic stress is not clearly defined, even though the kinase has been shown to play a crucial role in the functional maintenance of organelles such as mitochondria [10], centrosomes [11], nuclear envelope and nucleoli [12,13]
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