ATR signaling can drive cells into senescence in the absence of DNA breaks
Luis I Toledo1, Matilde Murga, Paula Gutierrez-Martinez
1Genomic Instability Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
Abstract:
The ATR kinase is a key transducer of "replicative stress," the type of genomic damage that has been postulated to be induced by oncogenes. Here we describe a cellular system in which we can unleash ATR activity at will, in the absence of any actual damage or additional signaling pathways triggered by DNA breaks. We demonstrate that activating ATR is sufficient to promote cell cycle arrest and, if persistent, triggers p53-dependent but Ink4a/ARF-independent senescence. Moreover, we show that an ectopic activation of ATR leads to a G1/S arrest in ATM-/- cells, providing the first evidence of functional complementation of ATM deficiency by ATR. Our system provides a novel platform for the study of the specific functions of ATR signaling and adds evidence for the tumor-suppressive potential of the DNA damage response.
Insights
Activating ATR kinase, a key player in genomic damage response, can induce cell cycle arrest and senescence. This study shows ATR can functionally complement ATM deficiency, highlighting its tumor-suppressive potential.
Area of Science:
- Cellular biology
- Genomics
- Molecular oncology
Background:
- The ATR kinase is a critical mediator of replicative stress, a form of genomic damage implicated in oncogene activation.
- Understanding ATR's specific functions is crucial for cancer research and therapeutic development.
Purpose of the Study:
- To develop a cellular system to study ATR kinase activity independently of DNA damage.
- To investigate the consequences of ATR activation on cell cycle progression and senescence.
- To explore ATR's role in complementing ATM deficiency.
Main Methods:
- Development of a novel cellular system allowing inducible ATR activation.
- Analysis of cell cycle progression following ATR activation.
- Assessment of senescence induction and its dependence on p53 and Ink4a/ARF pathways.
- Evaluation of ATR's effect on ATM-deficient cells (ATM-/-).
Main Results:
- Inducible ATR activation is sufficient to cause cell cycle arrest.
- Persistent ATR activation triggers p53-dependent, Ink4a/ARF-independent senescence.
- Ectopic ATR activation rescues G1/S arrest in ATM-/- cells, demonstrating functional complementation.
Conclusions:
- The developed system provides a platform for dissecting ATR signaling pathways.
- ATR activation alone can induce cell cycle arrest and senescence.
- ATR plays a role in functionally complementing ATM deficiency, suggesting a broader role in DNA damage response and tumor suppression.
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