NOTCH1-driven UBR7 stimulates nucleotide biosynthesis to promote T cell acute lymphoblastic leukemia

Sci Adv. 2021 Jan 27;7(5):eabc9781. doi: 10.1126/sciadv.abc9781. Print 2021 Jan.


Ubiquitin protein ligase E3 component N-recognin 7 (UBR7) is the most divergent member of UBR box-containing E3 ubiquitin ligases/recognins that mediate the proteasomal degradation of its substrates through the N-end rule. Here, we used a proteomic approach and found phosphoribosyl pyrophosphate synthetases (PRPSs), the essential enzymes for nucleotide biosynthesis, as strong interacting partners of UBR7. UBR7 stabilizes PRPS catalytic subunits by mediating the polyubiquitination-directed degradation of PRPS-associated protein (PRPSAP), the negative regulator of PRPS. Loss of UBR7 leads to nucleotide biosynthesis defects. We define UBR7 as a transcriptional target of NOTCH1 and show that UBR7 is overexpressed in NOTCH1-driven T cell acute lymphoblastic leukemia (T-ALL). Impaired nucleotide biosynthesis caused by UBR7 depletion was concomitant with the attenuated cell proliferation and oncogenic potential of T-ALL. Collectively, these results establish UBR7 as a critical regulator of nucleotide metabolism through the regulation of the PRPS enzyme complex and uncover a metabolic vulnerability in NOTCH1-driven T-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Nucleotides* / biosynthesis
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Proteomics
  • Receptor, Notch1* / genetics
  • Receptor, Notch1* / metabolism
  • T-Lymphocytes / pathology
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism
  • Ubiquitination


  • NOTCH1 protein, human
  • Nucleotides
  • Receptor, Notch1
  • UBR7 protein, human
  • Ubiquitin-Protein Ligases