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Updated: May 21, 2025

Purification of Ubiquitinated p53 Proteins from Mammalian Cells
10:55

Purification of Ubiquitinated p53 Proteins from Mammalian Cells

Published on: March 21, 2022

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Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality

Xiang-Le Zhang1,2, Hong-Wei Yue1,2, Ya-Jun Liu1,2

  • 1Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China.

Iscience
|March 19, 2025
PubMed

Insights

Engineered polyQ fusion proteins can sequester USP7 and HDM2, reactivating P53 signaling. This strategy shows therapeutic potential for cancer by modulating P53 stability and function.

Area of Science:

  • Oncology
  • Molecular Biology
  • Protein Engineering

Background:

  • Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells, promoting cancer progression.
  • Targeting USP7 and HDM2 to restore P53 function is a significant challenge in cancer therapy.

Purpose of the Study:

  • To engineer polyQ fusion proteins for specific sequestration of USP7 and HDM2.
  • To modulate P53 stability and functionality through targeted protein aggregation.

Main Methods:

  • Design and application of polyQ sequences fused with target-interacting peptides.
  • Engineering of designer fusion proteins, such as Atx793Q-N172-IRF and Atx793Q-N172-PMI.
  • Analysis of P53 level modulation and downstream gene expression.

Main Results:

  • The fusion protein Atx793Q-N172-IRF sequesters USP7 and/or HDM2, increasing P53 levels, with effects dependent on IRF repeats.
  • Depletion of USP7 availability by fusion proteins plays a dual role in controlling P53 stability.
  • Direct sequestration of HDM2 by Atx793Q-N172-PMI significantly reduces soluble HDM2, increasing P53 levels and up-regulating downstream gene expression.

Conclusions:

  • The polyQ-fusion strategy is a feasible approach to modulate P53 stability and functionality.
  • Engineered polyQ fusion proteins demonstrate therapeutic potential for cancer treatment by targeting USP7 and HDM2.
Keywords:
BiochemistryCancerProtein structure aspects

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