title: Replication stress and chromatin context link ATM activation to a role in DNA replication.
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.
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Olcina
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Iosifina P
authors.initials: IP
authors.lastname: Foskolou
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Anbalagan
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Joana M
authors.initials: JM
authors.lastname: Senra
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Pires
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK. Electronic address: ester.hammond@oncology.ox.ac.uk.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D057809:HEK293 Cells; D006570:Heterochromatin / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D064007:Ataxia Telangiectasia Mutated Proteins