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

Shashank Srivastava, Umakant Sahu, Yalu Zhou, Ann K. Hogan, Kizhakke Mattada Sathyan, Justin Bodner, Jiehuan Huang, Kelvin A. Wong, Natalia Khalatyan, Jeffrey N. Savas, Panagiotis Ntziachristos, Issam Ben-Sahra, Daniel R. Foltz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numberabc9781
JournalScience Advances
Volume7
Issue number5
DOIs
StatePublished - Jan 27 2021

ASJC Scopus subject areas

  • General

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