期刊
SCIENCE ADVANCES
卷 7, 期 5, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abc9781
关键词
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资金
- Zell Scholarship from the Robert H. Lurie Comprehensive Cancer Center, Northwestern University
- NICHD [1R21HD078946]
- NCI [CA 248770]
UBR7 interacts with phosphoribosyl pyrophosphate synthetases (PRPSs) and stabilizes them to regulate nucleotide biosynthesis. UBR7 is a transcriptional target of NOTCH1 and its overexpression is associated with T-ALL. Depletion of UBR7 impairs nucleotide biosynthesis leading to reduced cell proliferation and oncogenic potential in T-ALL.
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.
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