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RESEARCH COMMUNICATION

ATR signaling can drive cells into senescence in the absence of DNA breaks

Genomic Instability Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain

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.

[Keywords: ATR; DNA damage response; senescence; ARF; p53]]

Received August 10, 2007; revised version accepted November 30, 2007.

E-MAIL ofernandez{at}cnio.es; FAX 34-91-7328033.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.452308

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