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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

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Cytoplasmic E3 ubiquitin ligase CUL9 controls cell proliferation, senescence, apoptosis and genome integrity through

Z Li1, Y Xiong1,2

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Oncogene
|May 9, 2017
PubMed

Insights

Cullin 9 (CUL9) is a critical activator of the tumor suppressor p53. Loss of CUL9 function impairs DNA damage response and promotes genomic instability, primarily through its interaction with p53.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Cullin 9 (CUL9) is an E3 ubiquitin ligase predominantly found in the cytoplasm.
  • CUL9 deletion in mice leads to increased DNA damage, aneuploidy, and tumor development.
  • CUL9 interacts with p53, suggesting a potential role in p53-mediated apoptosis.

Purpose of the Study:

  • To genetically investigate the link between CUL9's function in genomic integrity and tumor suppression, and its interaction with p53.
  • To elucidate the role of CUL9-p53 binding in cellular responses to DNA damage and proliferation.

Main Methods:

  • Deletion of CUL9 in human cells to assess DNA damage response.
  • Generation of a knock-in mouse embryo fibroblast (MEF) model with disrupted Cul9-p53 binding (Cul9Δp53).
  • Comparison of Cul9-/-, Cul9Δp53, and p53-/- MEFs for DNA damage accumulation, cell cycle progression, and apoptosis.

Main Results:

  • CUL9 deletion in human cells resulted in reduced p21 induction and impaired DNA damage response.
  • Cul9Δp53 MEFs exhibited increased DNA damage during replication, reduced apoptosis, and elevated S-phase populations, similar to Cul9-/- and p53-/- MEFs.
  • CUL9 deletion did not further increase DNA damage in p53 null cells, indicating p53-dependence.
  • Both Cul9-/- and Cul9Δp53 MEFs showed faster proliferation and spontaneous immortalization.

Conclusions:

  • CUL9's role in regulating cell proliferation and maintaining genomic integrity is largely mediated through its interaction with p53.
  • CUL9 functions as a critical activator of p53, influencing its tumor-suppressive functions.
  • Disruption of CUL9-p53 binding phenocopies the effects of CUL9 or p53 loss on genomic stability and proliferation.

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