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

Mol Cell. 2014 Feb 6;53(3):458-70. doi: 10.1016/j.molcel.2013.12.017. Epub 2014 Jan 23.


Nucleotide biosynthesis is fundamental to normal cell proliferation as well as to oncogenesis. Tumor suppressor p53, which prevents aberrant cell proliferation, is destabilized through ubiquitylation by MDM2. Ubiquitin-specific protease 7 (USP7) plays a dualistic role in p53 regulation and has been proposed to deubiquitylate either p53 or MDM2. Here, we show that guanosine 5'-monophosphate synthase (GMPS) is required for USP7-mediated stabilization of p53. Normally, most GMPS is sequestered in the cytoplasm, separated from nuclear USP7 and p53. In response to genotoxic stress or nucleotide deprivation, GMPS becomes nuclear and facilitates p53 stabilization by promoting its transfer from MDM2 to a GMPS-USP7 deubiquitylation complex. Intriguingly, cytoplasmic sequestration of GMPS requires ubiquitylation by TRIM21, a ubiquitin ligase associated with autoimmune disease. These results implicate a classic nucleotide biosynthetic enzyme and a ubiquitin ligase, better known for its role in autoimmune disease, in p53 control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Breast Neoplasms / metabolism
  • Carbon-Nitrogen Ligases / analysis
  • Carbon-Nitrogen Ligases / genetics
  • Carbon-Nitrogen Ligases / metabolism
  • Carbon-Nitrogen Ligases / physiology*
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Damage
  • Drosophila / genetics
  • Female
  • HEK293 Cells
  • Humans
  • Nucleotides / biosynthesis*
  • Ribonucleoproteins / metabolism
  • Ribonucleoproteins / physiology*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin Thiolesterase / physiology
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination


  • Nucleotides
  • Ribonucleoproteins
  • SS-A antigen
  • Tumor Suppressor Protein p53
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7
  • Carbon-Nitrogen Ligases
  • GMP synthase (glutamine-hydrolyzing)