There was an error published in J. Cell Sci. 128, 4255-4262.An incorrect citation and reference was given for the last sentence in Box 2. The correct citation and reference are: A recent review provides a detailed update on ATM and ATR inhibitors, and their potential as drug targets (Weber and Ryan, 2015).Weber, A.M. and Ryan, A.J. (2015). ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 149, 124-138.The authors apologise to the readers for any confusion that this error might have caused. Although the role of both ATM and ATR in DNA repair, cell cycle regulation and apoptosis have been well studied, both still remain in the focus of current research activities owing to their role in cancer. Recent advances in the field suggest that these proteins have an additional function in maintaining cellular homeostasis under both stressed and non-stressed conditions. In this Cell Science at a Glance article and the accompanying poster, we present an overview of recent advances in ATR and ATM research with emphasis on that into the modes of ATM and ATR activation, the different signaling pathways they participate in -including those that do not involve DNA damage -and highlight their relevance in cancer. 1285
SummaryATR controls chromosome integrity and chromatin dynamics. We have previously shown that yeast Mec1/ATR promotes chromatin detachment from the nuclear envelope to counteract aberrant topological transitions during DNA replication. Here, we provide evidence that ATR activity at the nuclear envelope responds to mechanical stress. Human ATR associates with the nuclear envelope during S phase and prophase, and both osmotic stress and mechanical stretching relocalize ATR to nuclear membranes throughout the cell cycle. The ATR-mediated mechanical response occurs within the range of physiological forces, is reversible, and is independent of DNA damage signaling. ATR-defective cells exhibit aberrant chromatin condensation and nuclear envelope breakdown. We propose that mechanical forces derived from chromosome dynamics and torsional stress on nuclear membranes activate ATR to modulate nuclear envelope plasticity and chromatin association to the nuclear envelope, thus enabling cells to cope with the mechanical strain imposed by these molecular processes.
Class I phosphoinositide 3-kinases are enzymes that generate 3-poly-phosphoinositides at the cell membrane following transmembrane receptor stimulation. Expression of the phosphoinositide 3-kinase β (PI3Kβ) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kβ in the cell remains elusive. Double-strand breaks (DSB) are among the most deleterious lesions for genomic integrity; their repair is required for development. We show that PI3Kβ is necessary for DSB sensing, as PI3Kβ regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kβ-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kβ also retarded the DNA repair but the defect was less marked than that induced by PI3Kβ deletion, supporting a kinase-independent function for PI3Kβ in DNA repair. These results point at class I PI3Kβ as a critical sensor of genomic integrity.
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