4.4 Article

XPC promotes MDM2-mediated degradation of the p53 tumor suppressor

Journal

MOLECULAR BIOLOGY OF THE CELL
Volume 25, Issue 2, Pages 213-221

Publisher

AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E13-05-0293

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Funding

  1. National Institutes of Health [GM 078085, P30 CA054174]
  2. Welch Foundation [AQ-1747]
  3. U.S. Department of Defense [W911NF-11-10466]
  4. Fudan University Key Laboratory Visiting Scholarship
  5. National Science and Technology Key Program of China [2009ZX09301-011]
  6. National Basic Science Research Program of China [2010CB912602]

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Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis.

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