ATM activation and signaling under hypoxic conditions

Bencokova, Zuzana; Kaufmann, Muriel R.; Monteiro dos Santos Pires, Isabel; Pires, Isabel M.; Lecane, Philip S.; Giaccia, Amato J.; Hammond, Ester M.

Abstract

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.

Citation

Bencokova, Z., Kaufmann, M. R., Monteiro dos Santos Pires, I., Lecane, P. S., Giaccia, A. J., & Hammond, E. M. (2009). ATM activation and signaling under hypoxic conditions. Molecular and cellular biology, 29(2), 526-537. https://doi.org/10.1128/MCB.01301-08

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2008
• Online Publication Date: Nov 3, 2008
• Publication Date: Jan 1, 2009
• Journal: MOLECULAR AND CELLULAR BIOLOGY
• Print ISSN: 0270-7306
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 2
• Pages: 526-537
• DOI: https://doi.org/10.1128/MCB.01301-08
• Keywords: Cell Biology; Molecular Biology
• Public URL: https://hull-repository.worktribe.com/output/417508
• Publisher URL: https://mcb.asm.org/content/29/2/526