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

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...

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Published in:	Molecular cell Vol. 52; no. 5; p. 758
Main Authors:	Olcina, Monica M, Foskolou, Iosifina P, Anbalagan, Selvakumar, Senra, Joana M, Pires, Isabel M, Jiang, Yanyan, Ryan, Anderson J, Hammond, Ester M
Format:	Journal Article
Language:	English
Published:	United States 12.12.2013
Subjects:	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
ISSN:	1097-4164, 1097-4164
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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.
AbstractList	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. 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.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.
Author	Pires, Isabel M Hammond, Ester M Olcina, Monica M Senra, Joana M Foskolou, Iosifina P Anbalagan, Selvakumar Ryan, Anderson J Jiang, Yanyan
Author_xml	– sequence: 1 givenname: Monica M surname: Olcina fullname: Olcina, Monica M organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 2 givenname: Iosifina P surname: Foskolou fullname: Foskolou, Iosifina P organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 3 givenname: Selvakumar surname: Anbalagan fullname: Anbalagan, Selvakumar organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 4 givenname: Joana M surname: Senra fullname: Senra, Joana M organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 5 givenname: Isabel M surname: Pires fullname: Pires, Isabel M organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 6 givenname: Yanyan surname: Jiang fullname: Jiang, Yanyan organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 7 givenname: Anderson J surname: Ryan fullname: Ryan, Anderson J organization: The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK – sequence: 8 givenname: Ester M surname: Hammond fullname: Hammond, Ester M email: ester.hammond@oncology.ox.ac.uk organization: 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
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SubjectTerms	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
Title	Replication stress and chromatin context link ATM activation to a role in DNA replication
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