A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN

• Published in: Cell reports (Cambridge) 2016-04, Vol.15 (4), p.893-908
• Main Authors: Mazouzi, Abdelghani, Stukalov, Alexey, Müller, André C., Chen, Doris, Wiedner, Marc, Prochazkova, Jana, Chiang, Shih-Chieh, Schuster, Michael, Breitwieser, Florian P., Pichlmair, Andreas, El-Khamisy, Sherif F., Bock, Christoph, Kralovics, Robert, Colinge, Jacques, Bennett, Keiryn L., Loizou, Joanna I.
• Format: Article
• Language: English
• Subjects: ATM; ATMIN; CRMP2; gene regulation; Human health and pathology; Life Sciences; phosphoproteomics; replication stress; γH2AX
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.03.077

The cellular response to replication stress requires the DNA-damage-responsive kinase ATM and its cofactor ATMIN; however, the roles of this signaling pathway following replication stress are unclear. To identify the functions of ATM and ATMIN in response to replication stress, we utilized both transcriptomics and quantitative mass-spectrometry-based phosphoproteomics. We found that replication stress induced by aphidicolin triggered widespread changes in both gene expression and protein phosphorylation patterns. These changes gave rise to distinct early and late replication stress responses. Furthermore, our analysis revealed previously unknown targets of ATM and ATMIN downstream of replication stress. We demonstrate ATMIN-dependent phosphorylation of H2AX and of CRMP2, a protein previously implicated in Alzheimer’s disease but not in the DNA damage response. Overall, our dataset provides a comprehensive resource for discovering the cellular responses to replication stress and, potentially, associated pathologies. [Display omitted] •Replication stress triggers widespread changes in phosphorylation and expression•ATM-ATMIN regulate phosphorylation events and expression upon replication stress•ATMIN modulates the phosphorylation of H2AX and CRMP2 following replication stress•Replication-stress-induced phosphorylation of CRMP2 regulates genome stability The global cellular response to replication stress is poorly understood. To elucidate the contribution of ATM-ATMIN signaling to the replication stress response, Mazouzi et al. combine phosphoproteomics and transcriptomics. They identify known and novel events, including the phosphorylation of CRMP2, a protein implicated in Alzheimer’s disease but not in the DNA damage response.