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

Makoto R. Hara, Jeffrey J. Kovacs, Erin J. Whalen, Sudarshan Rajagopal, Ryan T. Strachan, Wayne Grant, Aaron J. Towers, Barbara Williams, Christopher M. Lam, Kunhong Xiao, Sudha K. Shenoy, Simon G. Gregory, Seungkirl Ahn, Derek R. Duckett and Robert J. Lefkowitz ()
Additional contact information
Makoto R. Hara: Duke University Medical Center
Jeffrey J. Kovacs: Duke University Medical Center
Erin J. Whalen: Duke University Medical Center
Sudarshan Rajagopal: Duke University Medical Center
Ryan T. Strachan: Duke University Medical Center
Wayne Grant: Translational Research Institute, The Scripps Research Institute
Aaron J. Towers: Duke University Medical Center
Barbara Williams: Duke University Medical Center
Christopher M. Lam: Duke University Medical Center
Kunhong Xiao: Duke University Medical Center
Sudha K. Shenoy: Duke University Medical Center
Simon G. Gregory: Duke University Medical Center
Seungkirl Ahn: Duke University Medical Center
Derek R. Duckett: Translational Research Institute, The Scripps Research Institute
Robert J. Lefkowitz: Duke University Medical Center

Nature, 2011, vol. 477, issue 7364, 349-353

Abstract: DNA damage build-up in chronic stress Chronic stress is thought to lead to DNA damage, but the mechanisms involved are unclear. Here a molecular pathway is elucidated whereby stress-hormone activation of β2-adrenoreceptors triggers DNA damage and suppression of p53 levels through Gs-PKA and β-arrestin-1 signalling pathways. Cytosolic β-arrestin-1 facilitates activation of the E3 ligase Mdm2 by AKT, while nuclear β-arrestin-1 promotes Mdm2-mediated ubiquitination and degradation of p53. These results highlight the emerging role of β-arrestin-1 as an E3-ligase adaptor in the nucleus and reveal how DNA damage may accumulate in response to chronic stress.

Date: 2011
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DOI: 10.1038/nature10368

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