Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen
Alexander J Stuart1, Kaori K Takai1, Railia R Gabbasova2
1Laboratory for Cell Biology and Genetics, New York, NY, USA.
Abstract:
Replicative senescence is a powerful tumor suppressor pathway that curbs proliferation of human cells when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (∼20%) oxygen, primary fibroblast cells grown at physiological (3%) oxygen were more tolerant to critically short telomeres, explaining their extended replicative lifespan. We show that this tolerance is due to attenuation of the ATM response to double-strand breaks (DSBs) and unprotected telomeres. Our data indicate that the reduced ATM response to DSBs at 3% oxygen is due to increased ROS, which induces disulfide crosslinked ATM dimers that do not respond to DSBs. This regulation of cellular lifespan through attenuation of ATM at physiological oxygen has implications for tumor suppression through telomere shortening.
Insights
ATM kinase drives cellular senescence by sensing short telomeres. Physiological oxygen levels attenuate ATM activity, extending cell lifespan and impacting tumor suppression via telomere shortening.
Area of Science:
- Cellular Biology
- Oncology
- Genetics
Background:
- Replicative senescence is a tumor suppressor mechanism triggered by critically short telomeres activating the DNA damage response (DDR).
- ATM (ataxia-telangiectasia mutated) is a key kinase in the DDR pathway.
Purpose of the Study:
- To identify the specific DDR kinase responsible for replicative senescence.
- To investigate the role of oxygen levels in cellular lifespan and ATM activity.
- To elucidate the mechanism by which physiological oxygen affects ATM response to DNA damage.
Main Methods:
- Utilized primary fibroblast cells cultured at physiological (3%) and atmospheric (20%) oxygen levels.
- Assessed the role of ATM kinase in inducing and maintaining replicative senescence.
- Investigated ATM response to double-strand breaks (DSBs) and unprotected telomeres under different oxygen conditions.
- Analyzed the effect of reactive oxygen species (ROS) on ATM dimer formation and activity.
Main Results:
- ATM was identified as the sole DDR kinase essential for inducing and maintaining replicative senescence.
- ATM inhibition restored normal cell division in senescent cells.
- Primary fibroblasts exhibited extended replicative lifespan at 3% oxygen compared to 20% oxygen.
- This extended lifespan at 3% oxygen was attributed to an attenuated ATM response to DSBs and unprotected telomeres.
- Increased ROS at 3% oxygen led to disulfide-crosslinked ATM dimers, impairing ATM response to DSBs.
Conclusions:
- ATM kinase is the central regulator of replicative senescence.
- Physiological oxygen levels attenuate ATM signaling, prolonging cellular lifespan.
- This oxygen-mediated regulation of ATM activity has significant implications for telomere-driven tumor suppression.
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