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...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2013
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| _version_ | 1826264638427234304 |
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| author | Olcina, M Foskolou, I Anbalagan, S Senra, J Pires, I Jiang, Y Ryan, A Hammond, E |
| author_facet | Olcina, M Foskolou, I Anbalagan, S Senra, J Pires, I Jiang, Y Ryan, A Hammond, E |
| author_sort | Olcina, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:11:03Z |
| format | Journal article |
| id | oxford-uuid:2a917c47-6904-4689-9711-c57b66b725bf |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:11:03Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:2a917c47-6904-4689-9711-c57b66b725bf2022-03-26T12:25:45ZReplication stress and chromatin context link ATM activation to a role in DNA replication.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2a917c47-6904-4689-9711-c57b66b725bfEnglishSymplectic Elements at Oxford2013Olcina, MFoskolou, IAnbalagan, SSenra, JPires, IJiang, YRyan, AHammond, EATM-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. |
| spellingShingle | Olcina, M Foskolou, I Anbalagan, S Senra, J Pires, I Jiang, Y Ryan, A Hammond, E Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title | Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title_full | Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title_fullStr | Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title_full_unstemmed | Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title_short | Replication stress and chromatin context link ATM activation to a role in DNA replication. |
| title_sort | replication stress and chromatin context link atm activation to a role in dna replication |
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