Abstract
ATM responds to replication stress and hypoxia-induced H3K9me3 in the absence of DNA damage.
Major finding: ATM responds to replication stress and hypoxia-induced H3K9me3 in the absence of DNA damage.
Mechanism: Stress-mediated ATM activation maintains DNA replication and prevents DNA damage accumulation.
Impact: Hypoxia and replication stress may cooperate to induce ATM as an early barrier to tumorigenesis.
Exposure to severe hypoxia triggers DNA replication stress and results in activation of the DNA damage response (DDR), which preserves replication fork integrity and aids subsequent reoxygenation-induced replication restart. Recent studies have shown that hypoxia also activates ataxia telangiectasia mutated (ATM), a critical mediator of the DDR that suppresses tumorigenesis, via phosphorylation in the absence of DNA damage; however, the role of ATM in the response to replication stress remains unclear. Olcina and colleagues found that hypoxia-induced replication stress stimulated phosphorylation of ATM and its downstream target KAP1 (also known as tripartite motif containing 28) in S phase, suggesting that ATM responds to replication stress. In addition, hypoxia-induced ATM activation was context specific and dependent on the presence of the heterochromatic mark histone H3 Lys9 trimethylation (H3K9me3), which was globally elevated under hypoxia, including around replication forks, and repressed the expression of the ATM-specific phosphatase protein phosphatase 2A. Depletion or pharmacologic inhibition of ATM in hypoxic cells resulted in increased DNA damage and reduced replication rates, supporting a stress-specific role for ATM in preserving replication fork integrity, maintaining DNA replication, and preventing DNA damage accumulation under hypoxia. Furthermore, replication stress induced by alternative means, such as hydroxyurea or oncogenic KRAS expression, enhanced ATM activation under less severe hypoxic conditions sufficient to trigger increased H3K9me3 levels but not replication stress and in the absence of DNA damage. These results identify ATM as a specific and critical mediator of the response to replication stress in heterochromatin-rich areas and suggest that hypoxia-mediated chromatin changes and replication stress may cooperate to trigger ATM activation as an early barrier to inhibit tumorigenesis.