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Published on: August 12, 2018
ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels
Kelly D Sullivan1, Vignesh V Palaniappan, Joaquín M Espinosa
1a Howard Hughes Medical Institute and Department of Molecular; Cellular and Developmental Biology ; University of Colorado ; Boulder , CO USA.
Abstract:
Despite extensive study, the mechanisms of cell fate choice upon p53 activation remain poorly understood. Using genome-wide shRNA screening, we recently identified the ATM kinase as synthetic lethal with Nutlin-3, an MDM2 inhibitor that leads to non-genotoxic p53 activation. Here, we demonstrate that while this synthetic lethal interaction relies upon components of both the intrinsic and extrinsic apoptotic pathways (e.g., BAX and BID), it is not due to significant ATM effects on the expression of p53 target genes. Instead, loss of ATM activity results in increased mitochondria and reactive oxygen species that drive apoptosis. Finally, we provide evidence that pharmacologic inhibition of ATM blocks autophagy in direct opposition to p53, which activates this process, and that inhibition of autophagy is sufficient to elicit an apoptotic response when combined with Nutlin-3.
Insights
ATM kinase inhibition, combined with MDM2 inhibitor Nutlin-3, triggers cell death by increasing mitochondrial reactive oxygen species and blocking autophagy, revealing new insights into p53-mediated cell fate.
Area of Science:
- Cell Biology
- Molecular Oncology
- Apoptosis and Autophagy Pathways
Background:
- Mechanisms governing cell fate decisions following p53 activation are not fully elucidated.
- ATM kinase was identified as synthetically lethal with Nutlin-3, an MDM2 inhibitor inducing non-genotoxic p53 activation.
Purpose of the Study:
- To investigate the mechanistic basis of the synthetic lethality between ATM inhibition and Nutlin-3.
- To explore the role of ATM in p53-mediated cell fate decisions, focusing on apoptosis and autophagy.
Main Methods:
- Genome-wide shRNA screening to identify synthetic lethal interactions.
- Analysis of apoptotic pathway components (BAX, BID) and p53 target gene expression.
- Assessment of mitochondrial activity, reactive oxygen species (ROS) production, and autophagy modulation.
Main Results:
- The synthetic lethal interaction between ATM and Nutlin-3 depends on apoptotic factors like BAX and BID but not significantly on p53 target gene expression.
- Loss of ATM activity leads to elevated mitochondrial ROS, promoting apoptosis.
- Pharmacologic ATM inhibition counteracts p53-induced autophagy; blocking autophagy potentiates Nutlin-3-induced apoptosis.
Conclusions:
- ATM loss sensitizes cells to Nutlin-3 via increased mitochondrial ROS and apoptosis, independent of direct p53 target gene regulation.
- ATM inhibition opposes p53's pro-autophagy function, and inhibiting autophagy is sufficient to induce apoptosis in combination with Nutlin-3.
- This study reveals a novel interplay between ATM, mitochondria, ROS, autophagy, and p53 in determining cell fate.
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