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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Vydáno v:Molecular cell Ročník 52; číslo 5; s. 758
Hlavní autoři: Olcina, Monica M, Foskolou, Iosifina P, Anbalagan, Selvakumar, Senra, Joana M, Pires, Isabel M, Jiang, Yanyan, Ryan, Anderson J, Hammond, Ester M
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 12.12.2013
Témata:
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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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2013.10.019