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Stress Fractures in DNA

Prolonged adrenergic stimulation results in DNA damage through a β-arrestin1–dependent pathway. The catecholamines adrenaline and noradrenaline trigger a “fight-or-flight” response by activating adrenergic receptors, such as the β2-adrenergic receptor. However, prolonged adrenergic stimulation can cause various deleterious physiological effects, and epidemiological studies have associated chronic stress with DNA damage. To investigate the mechanisms by which prolonged adrenergic stimulation may cause DNA damage, Hara et al. injected the β2-adrenergic receptor agonist isoproterenol into mice for 4 weeks to simulate chronic stress. The thymuses of isoproterenol-injected mice showed increased phosphorylation of histone H2AX (γ-H2AX), a marker of DNA damage, and decreased abundance of the transcription factor p53, which functions in cellular responses to stress. Similarly, U2OS cells, in which β2-adrenergic receptors are the only detectable adrenergic receptor, showed decreased p53 abundance when treated with isoproterenol, a response that was attenuated by preincubating the cells with the β2-adrenergic receptor antagonist ICI 118,551. Isoproterenol infusion resulted in DNA damage in the cerebellum in wild-type mice but not in mice lacking the gene encoding the β2-adrenergic receptor (Adrb2–/– mice). The ubiquitin ligase Mdm2 targets p53 for proteasomal degradation, and isoproterenol stimulated phosphorylation and activation of Mdm2 through a pathway that required β-arrestin1, phosphoinositide 3-kinase (PI3K), and the kinase AKT. β-arrestin1 interacted with p53 in the nucleus and appeared necessary to enhance the interaction of p53 with Mdm2 after isoproterenol stimulation. Mouse embryo fibroblasts (MEFs) lacking β-arrrestin1 (Arrb1–/–) showed lower numbers of γ-H2AX foci and higher abundance of p53 than wild-type MEFs, and Arrb1–/– mice were protected from DNA damage (as shown by the amount of γ-H2AX and the number of chromosomal rearrangements) and the reduction in p53 abundance elicited by isoproterenol infusion. Thus, chronic stress may elicit DNA damage and reduced p53 abundance through β2-adrenergic receptor–mediated activation of a β-arrestin1–dependent pathway. M. R. Hara, J. J. Kovacs, E. J. Whalen, S. Rajagopal, R. T. Strachan, W. Grant, A. J. Towers, B. Williams, C. M. Lam, K. Xiao, S. K. Shenoy, S. G. Gregory, S. Ahn, D. R. Duckett, R. J. Lefkowitz, A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477, 349–353 (2011). [PubMed]