ReviewThe DNA damage response, immunity and cancer
Section snippets
Surveillance against DNA damage
Maintenance of genome integrity after DNA damage is vital for eukaryotic cells. A failure can endanger the survival of the individual cell as well as of the organism. Following DNA damage, the PI3-kinase-relateded protein kinases ATM (Ataxia Telangiectasia, mutated) and ATR (ATM- and Rad3-Related) cooperate with other proteins to initiate the DNA damage response [4]. Double-strand breaks preferentially activate ATM, whereas stalled DNA replication induces ATR activity. In response to many
The DNA damage response induces expression of ligands for the NKG2D receptor
Direct evidence for such a role of the DNA damage response was provided by our finding that DNA damaging agents or DNA replication inhibitors, but not other common forms of stress, induce expression of cell surface protein ligands for the NKG2D receptor in an ATM or ATR dependent fashion [3]. NKG2D is an activating receptor expressed on NK cells, subsets of γ/δ T cells, NKT cells, and cytotoxic CD8+ T cells [7], [8], [9]. In humans, all CD8+ T cells express NKG2D. In contrast, NKG2D expression
Conclusion
We have recently shown that ligands for the activating immune receptor NKG2D are induced by the DNA damage response, which is activated early in tumorigenesis as well as during certain virus infections. Genotoxic stress may therefore represent an important means by which the immune system distinguishes diseased cells from normal cells. The resulting activation of the DNA damage response would allow a cell to recognize the “danger” posed by diseased cells and trigger signals that induce
Acknowledgments
We would like to thank the members of the Raulet laboratory for helpful discussions. This work was supported by grants from the National Institutes of Health to D.H. Raulet.
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