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.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
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
Substances
-
NOTCH1 protein, human
-
Nucleotides
-
Receptor, Notch1
-
UBR7 protein, human
-
Ubiquitin-Protein Ligases