A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1

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The human mind and body respond to stress1, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the ‘fight-or-flight’ response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term2. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders3, and epidemiological studies strongly indicate that chronic stress leads to DNA damage4,5. This stress-induced DNA damage may promote ageing6, tumorigenesis4,7, neuropsychiatric conditions8,9 and miscarriages10. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β2-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos11. Activated β2-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right12. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs–PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β2-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1−/−) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress1, and in the testes, in which paternal stress may affect the offspring’s genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.

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Figure 1: Chronic catecholamine stimulation leads to p53 degradation and accumulation of DNA damage via ARRB1/AKT-mediated activation of MDM2.
Figure 2: ARRB1 functions as an E3 ligase adaptor for MDM2 and p53 upon catecholamine stimulation.
Figure 3: ARRB1 facilitates catecholamine-induced p53 degradation by MDM2.
Figure 4: Chronic catecholamine stimulation leads to accumulation of DNA damage by an ARRB1- and p53-dependent mechanism.


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R.J.L. is a Howard Hughes Medical Institute investigator. This work was supported by HL16037 and HL70631 (R.J.L.). We thank D. Addison and Q. Lennon for secretarial assistance; S. H. Snyder and M. A. Koldobskiy for providing p53 deletion constructs; B. K. Kobilka and H. A. Rockman for providing Adrb2−/− mice; M. C. Hung for providing the MDM2-S166D plasmid; A. K. Shukla, A. Kahsai, J. Kim, J. Sun, S. M. DeWire and N. Odajima for discussion and comments.

Author information

M.R.H. and R.J.L. designed experiments, directed the study and wrote the paper. M.R.H. performed most of the experiments, analysed the data and prepared the figures. R.J.L. supervised the study and provided financial support. J.J.K. performed some experiments, helped to analyse the data and helped to write the paper. E.J.W., S.R., K.X., S.K.S. and S.A. helped to analyse the data. E.J.W., S.R., R.T.S., B.W., C.M.L. and S.A. performed some experiments. A.J.T. and S.G.G. performed the array-CGH and helped to analyse the data. W.G. and D.R.D. helped to characterize the functionality of p53 and to analyse the data.

Correspondence to Robert J. Lefkowitz.

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