A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN
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 tran...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-04-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716303667 |
| _version_ | 1818131533576273920 |
|---|---|
| author | Abdelghani Mazouzi Alexey Stukalov André C. Müller Doris Chen Marc Wiedner Jana Prochazkova Shih-Chieh Chiang Michael Schuster Florian P. Breitwieser Andreas Pichlmair Sherif F. El-Khamisy Christoph Bock Robert Kralovics Jacques Colinge Keiryn L. Bennett Joanna I. Loizou |
| author_facet | Abdelghani Mazouzi Alexey Stukalov André C. Müller Doris Chen Marc Wiedner Jana Prochazkova Shih-Chieh Chiang Michael Schuster Florian P. Breitwieser Andreas Pichlmair Sherif F. El-Khamisy Christoph Bock Robert Kralovics Jacques Colinge Keiryn L. Bennett Joanna I. Loizou |
| author_sort | Abdelghani Mazouzi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T08:22:27Z |
| format | Article |
| id | doaj.art-e3ac3a1fc8264f9bb8f095b75131f772 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T08:22:27Z |
| publishDate | 2016-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e3ac3a1fc8264f9bb8f095b75131f7722022-12-22T01:14:38ZengElsevierCell Reports2211-12472016-04-0115489390810.1016/j.celrep.2016.03.077A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMINAbdelghani Mazouzi0Alexey Stukalov1André C. Müller2Doris Chen3Marc Wiedner4Jana Prochazkova5Shih-Chieh Chiang6Michael Schuster7Florian P. Breitwieser8Andreas Pichlmair9Sherif F. El-Khamisy10Christoph Bock11Robert Kralovics12Jacques Colinge13Keiryn L. Bennett14Joanna I. Loizou15CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaKrebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UKCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaMax Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyKrebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UKCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, AustriaThe 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.http://www.sciencedirect.com/science/article/pii/S2211124716303667replication stressphosphoproteomicsgene regulationATMATMINγH2AXCRMP2 |
| spellingShingle | Abdelghani Mazouzi Alexey Stukalov André C. Müller Doris Chen Marc Wiedner Jana Prochazkova Shih-Chieh Chiang Michael Schuster Florian P. Breitwieser Andreas Pichlmair Sherif F. El-Khamisy Christoph Bock Robert Kralovics Jacques Colinge Keiryn L. Bennett Joanna I. Loizou A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN Cell Reports replication stress phosphoproteomics gene regulation ATM ATMIN γH2AX CRMP2 |
| title | A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN |
| title_full | A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN |
| title_fullStr | A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN |
| title_full_unstemmed | A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN |
| title_short | A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN |
| title_sort | comprehensive analysis of the dynamic response to aphidicolin mediated replication stress uncovers targets for atm and atmin |
| topic | replication stress phosphoproteomics gene regulation ATM ATMIN γH2AX CRMP2 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716303667 |
| work_keys_str_mv | AT abdelghanimazouzi acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT alexeystukalov acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT andrecmuller acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT dorischen acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT marcwiedner acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT janaprochazkova acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT shihchiehchiang acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT michaelschuster acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT florianpbreitwieser acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT andreaspichlmair acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT sheriffelkhamisy acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT christophbock acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT robertkralovics acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT jacquescolinge acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT keirynlbennett acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT joannailoizou acomprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT abdelghanimazouzi comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT alexeystukalov comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT andrecmuller comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT dorischen comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT marcwiedner comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT janaprochazkova comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT shihchiehchiang comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT michaelschuster comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT florianpbreitwieser comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT andreaspichlmair comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT sheriffelkhamisy comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT christophbock comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT robertkralovics comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT jacquescolinge comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT keirynlbennett comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin AT joannailoizou comprehensiveanalysisofthedynamicresponsetoaphidicolinmediatedreplicationstressuncoverstargetsforatmandatmin |