Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization.
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.
Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
B Ashok
BA
Reddy
Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Jan A
JA
van der Knaap
Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Alice G M
AG
Bot
Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Adone
A
Mohd-Sarip
Proteomics Centre, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Dick H W
DH
Dekkers
Department of Medical Oncology, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Mieke A
MA
Timmermans
Department of Medical Oncology, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
John W M
JW
Martens
Proteomics Centre, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
Jeroen A A
JA
Demmers
Department of Biochemistry and Centre for Biomedical Genetics, Erasmus University Medical Centre, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands. Electronic address: c.verrijzer@erasmusmc.nl.
C Peter
CP
Verrijzer
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004330:Drosophila / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D009711:Nucleotides / Q000096:biosynthesis*; D012261:Ribonucleoproteins / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism / Q000502:physiology; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination; D000099207:SS-A Antigen
D019731:Carbon-Nitrogen Ligases; D009711:Nucleotides; D012261:Ribonucleoproteins; D016159:Tumor Suppressor Protein p53; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D000099207:SS-A Antigen; C464569:USP7 protein, human; C020828:GMP synthase (glutamine-hydrolyzing)