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

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

doi:10.1016/j.celrep.2016.03.077

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

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

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	893-908
Number of pages	16
Journal	Cell Reports
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2016.03.077
State	Published - 26 Apr 2016
Externally published	Yes

Keywords

ATM
ATMIN
CRMP2
Gene regulation
Phosphoproteomics
Replication stress
γH2AX

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10.1016/j.celrep.2016.03.077

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Mazouzi, A., Stukalov, A., Müller, A. C., Chen, D., Wiedner, M., Prochazkova, J., Chiang, S. C., Schuster, M., Breitwieser, F. P., Pichlmair, A., El-Khamisy, S. F., Bock, C., Kralovics, R., Colinge, J., Bennett, K. L., & Loizou, J. I. (2016). A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN. Cell Reports, 15(4), 893-908. https://doi.org/10.1016/j.celrep.2016.03.077

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

abstract = "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.",

keywords = "ATM, ATMIN, CRMP2, Gene regulation, Phosphoproteomics, Replication stress, γH2AX",

author = "Abdelghani Mazouzi and Alexey Stukalov and M{\"u}ller, {Andr{\'e} C.} and Doris Chen and Marc Wiedner and Jana Prochazkova and Chiang, {Shih Chieh} and Michael Schuster and Breitwieser, {Florian P.} and Andreas Pichlmair and El-Khamisy, {Sherif F.} and Christoph Bock and Robert Kralovics and Jacques Colinge and Bennett, {Keiryn L.} and Loizou, {Joanna I.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors..",

year = "2016",

month = apr,

day = "26",

doi = "10.1016/j.celrep.2016.03.077",

language = "English",

volume = "15",

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Mazouzi, A, Stukalov, A, Müller, AC, Chen, D, Wiedner, M, Prochazkova, J, Chiang, SC, Schuster, M, Breitwieser, FP, Pichlmair, A, El-Khamisy, SF, Bock, C, Kralovics, R, Colinge, J, Bennett, KL & Loizou, JI 2016, 'A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN', Cell Reports, vol. 15, no. 4, pp. 893-908. https://doi.org/10.1016/j.celrep.2016.03.077

TY - JOUR

T1 - A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN

AU - Mazouzi, Abdelghani

AU - Stukalov, Alexey

AU - Müller, André C.

AU - Chen, Doris

AU - Wiedner, Marc

AU - Prochazkova, Jana

AU - Chiang, Shih Chieh

AU - Schuster, Michael

AU - Breitwieser, Florian P.

AU - Pichlmair, Andreas

AU - El-Khamisy, Sherif F.

AU - Bock, Christoph

AU - Kralovics, Robert

AU - Colinge, Jacques

AU - Bennett, Keiryn L.

AU - Loizou, Joanna I.

PY - 2016/4/26

Y1 - 2016/4/26

N2 - 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.

AB - 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.

KW - ATM

KW - ATMIN

KW - CRMP2

KW - Gene regulation

KW - Phosphoproteomics

KW - Replication stress

KW - γH2AX

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M3 - Article

AN - SCOPUS:84963556584

SN - 2211-1247

VL - 15

SP - 893

EP - 908

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

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Keywords

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