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

Mol Cell. 2013 Dec 12;52(5):758-66. doi: 10.1016/j.molcel.2013.10.019. Epub 2013 Nov 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • Cell Hypoxia / genetics
  • Cell Line
  • DNA Damage
  • DNA Replication / genetics*
  • DNA-Binding Proteins / genetics
  • HEK293 Cells
  • Heterochromatin / genetics*
  • Histones / genetics
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Signal Transduction


  • DNA-Binding Proteins
  • Heterochromatin
  • Histones
  • Nuclear Proteins
  • Ataxia Telangiectasia Mutated Proteins