This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bencokova, Z.
Right arrow Articles by Hammond, E. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bencokova, Z.
Right arrow Articles by Hammond, E. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2009, p. 526-537, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01301-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ATM Activation and Signaling under Hypoxic Conditions {triangledown}

Zuzana Bencokova,1,{dagger} Muriel R. Kaufmann,1,{dagger} Isabel M. Pires,1 Philip S. Lecane,2,# Amato J. Giaccia,3 and Ester M. Hammond1*

Cancer Research UK/MRC Gray Institute for Radiation Oncology and Biology, Churchill Hospital, Oxford OX3 7LJ, United Kingdom,1 Pharmacyclics, Inc., Sunnyvale, California 94085,2 Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94303-51523

Received 15 August 2008/ Returned for modification 1 September 2008/ Accepted 26 October 2008

The ATM kinase has previously been shown to respond to the DNA damage induced by reoxygenation following hypoxia by initiating a Chk 2-dependent cell cycle arrest in the G2 phase. Here we show that ATM is both phosphorylated and active during exposure to hypoxia in the absence of DNA damage, detectable by either comet assay or 53BP1 focus formation. Hypoxia-induced activation of ATM correlates with oxygen concentrations low enough to cause a replication arrest and is entirely independent of hypoxia-inducible factor 1 status. In contrast to damage-activated ATM, hypoxia-activated ATM does not form nuclear foci but is instead diffuse throughout the nucleus. The hypoxia-induced activity of both ATM and the related kinase ATR is independent of NBS1 and MRE11, indicating that the MRN complex does not mediate the DNA damage response to hypoxia. However, the mediator MDC1 is required for efficient activation of Kap1 by hypoxia-induced ATM, indicating that similarly to the DNA damage response, there is a requirement for MDC1 to amplify the ATM response to hypoxia. However, under hypoxic conditions, MDC1 does not recruit BRCA1/53BP1 or RNF8 activity. Our findings clearly demonstrate that there are alternate mechanisms for activating ATM that are both stress-specific and independent of the presence of DNA breaks.

* Corresponding author. Mailing address: The Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Churchill Hospital, Oxford OX3 7DQ, United Kingdom. Phone: 01865 617320. Fax: 01865 617355. E-mail: Ester.Hammond{at}rob.ox.ac.uk

{triangledown} Published ahead of print on 3 November 2008.

{dagger} These authors contributed equally to this work.

# Present address: Syntaxin Ltd., Abingdon OX14 3YS, United Kingdom.

Molecular and Cellular Biology, January 2009, p. 526-537, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.01301-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»