Replication Stress and Chromatin Context Link ATM Activation to a Role in DNA Replication

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

doi:10.1016/j.molcel.2013.10.019

Monica M Olcina, Iosifina P Foskolou + Show 6 more

Open Access

https://doi.org/10.1016/j.molcel.2013.10.019

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Abstract

SummaryATM-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.

Highlights

Replication stress (RS) leads to fork stalling as a result of nucleotide pool depletion and/or the generation of DNA lesions (Murga et al, 2011)
ataxia-telangiectasia mutated (ATM)-mediated signaling in response to DNA damage is a barrier to tumorigenesis
In the absence of DNA damage, ATM responds to replication stress in a hypoxia-induced heterochromatin-like context

Summary

Introduction

Replication stress (RS) leads to fork stalling as a result of nucleotide pool depletion and/or the generation of DNA lesions (Murga et al, 2011). RS triggers a DNA damage response (DDR) in an attempt to resolve the insult, ensure fork integrity, and restart DNA synthesis (Harper and Elledge, 2007). The DDR is a complicated signaling cascade composed of sensors, transducers, and effectors that collectively orchestrate a response to the initial stress: RS or DNA single- or double-strand breaks (DSBs). ATM is present as an inactive dimer that becomes activated upon dissociation into monomers and intermolecular autophosphorylation on serine 1981 (Bakkenist and Kastan, 2003). Phosphatases such as PP2A and WIP-1 are important for the regulation of overall ATM activity following DNA damage (Goodarzi et al, 2004; Shreeram et al, 2006)

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