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

Author

Listed:
  • 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
    Center for Human Genetics, 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
    Center for Human Genetics, 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
    Howard Hughes Medical Institute, Duke University Medical Center)

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.

Suggested Citation

  • 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 & , 2011. "A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1," Nature, Nature, vol. 477(7364), pages 349-353, September.
    • Handle: RePEc:nat:nature:v:477:y:2011:i:7364:d:10.1038_nature10368
    DOI: 10.1038/nature10368
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