title: A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.
abstract: The human mind and body respond to stress, 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 term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-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 right. 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 β(2)-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 stress, 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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Makoto R
authors.initials: MR
authors.lastname: Hara
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kovacs
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Whalen
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Rajagopal
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Strachan
authors.forename: Wayne
authors.initials: W
authors.lastname: Grant
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Towers
authors.forename: Barbara
authors.initials: B
authors.lastname: Williams
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Lam
authors.forename: Kunhong
authors.initials: K
authors.lastname: Xiao
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Shenoy
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Seungkirl
authors.initials: S
authors.lastname: Ahn
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002395:Catecholamines / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage; D005347:Fibroblasts; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000502:physiology*; D013737:Testis / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D002395:Catecholamines; D018343:Receptors, Adrenergic, beta-2; D016159:Tumor Suppressor Protein p53; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases