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Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization

B Ashok Reddy1, Jan A van der Knaap1, Alice G M Bot1

  • 1Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.

Molecular Cell
|January 28, 2014
PubMed

Insights

Guiding nucleotide biosynthesis enzyme guanosine 5'-monophosphate synthase (GMPS) is crucial for stabilizing tumor suppressor p53. GMPS moves to the nucleus under stress, aiding p53 stabilization via a USP7 complex.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nucleotide biosynthesis is vital for cell proliferation and cancer.
  • Tumor suppressor p53 regulates cell growth but is destabilized by MDM2-mediated ubiquitylation.
  • Ubiquitin-specific protease 7 (USP7) influences p53 stability, potentially by deubiquitylating p53 or MDM2.

Purpose of the Study:

  • To investigate the role of guanosine 5'-monophosphate synthase (GMPS) in p53 regulation.
  • To elucidate the mechanism by which GMPS influences p53 stabilization.
  • To identify factors involved in GMPS localization and its interaction with the p53-MDM2-USP7 axis.

Main Methods:

  • Cellular localization studies of GMPS.
  • Analysis of p53 ubiquitylation and deubiquitylation.
  • Investigating protein-protein interactions using co-immunoprecipitation.
  • Assessing p53 stabilization under various stress conditions.

Main Results:

  • GMPS is essential for USP7-mediated p53 stabilization.
  • Genotoxic stress or nucleotide deprivation induces nuclear translocation of GMPS.
  • Nuclear GMPS facilitates p53 stabilization by mediating its transfer to a GMPS-USP7 deubiquitylation complex.
  • TRIM21-mediated ubiquitylation sequesters GMPS in the cytoplasm.

Conclusions:

  • GMPS plays a critical role in the p53 pathway, linking nucleotide metabolism to cell cycle control.
  • The localization of GMPS is a key regulatory step in p53 stabilization.
  • TRIM21, an E3 ubiquitin ligase implicated in autoimmune diseases, regulates GMPS localization and thus impacts p53 stability.

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