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Replication stress and chromatin context link ATM activation to a role in DNA replication

Olcina, Monica M.; Foskolou, Iosifina P.; Anbalagan, Selvakumar; Senra, Joana M.; Pires, Isabel M.; Jiang, Yanyan; Ryan, Anderson J.; Hammond, Ester M.

Authors

Monica M. Olcina

Iosifina P. Foskolou

Selvakumar Anbalagan

Joana M. Senra

Yanyan Jiang

Anderson J. Ryan

Ester M. Hammond



Contributors

Abstract

ATM-mediated signaling in response to DNA damage is a barrier to tumorigenesis. Here we asked whether replication stress could also contribute to ATM signaling. We demonstrate that, in the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context. In certain hypoxic conditions, replication stress occurs in the absence of detectable DNA damage. Hypoxia also induces H3K9me3, a histone modification associated with gene repression and heterochromatin. Hypoxia-induced replication stress together with increased H3K9me3 leads to ATM activation. Importantly, ATM prevents the accumulation of DNA damage in hypoxia. Most significantly, we describe a stress-specific role for ATM in maintaining DNA replication rates in a background of increased H3K9me3. Furthermore, the ATM-mediated response to oncogene-induced replication stress is enhanced in hypoxic conditions. Together, these data indicate that hypoxia plays a critical role in the activation of the DNA damage response, therefore contributing to this barrier to tumorigenesis.

Journal Article Type Article
Publication Date Nov 21, 2013
Journal Molecular Cell
Print ISSN 1097-2765
Electronic ISSN 1097-4164
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 52
Issue 5
Pages 758-766
Institution Citation Olcina, M. M., Foskolou, I. P., Anbalagan, S., Senra, J. M., Pires, I. M., Jiang, Y., …Hammond, E. M. (2013). Replication stress and chromatin context link ATM activation to a role in DNA replication. Molecular cell, 52(5), (758-766). doi:10.1016/j.molcel.2013.10.019. ISSN 1097-2765
DOI https://doi.org/10.1016/j.molcel.2013.10.019
Keywords Cell Biology; Molecular Biology
Publisher URL http://www.cell.com/molecular-cell/abstract/S1097-2765(13)00785-5
Copyright Statement This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Additional Information This article is maintained by: Elsevier; Article Title: Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication; Journal Title: Molecular Cell; CrossRef DOI link to publisher maintained version: http://dx.doi.org/10.1016/j.molcel.2013.10.019; Content Type: article; Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc.

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Copyright Statement
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.



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