ZBTB1 Regulates Asparagine Synthesis and Leukemia Cell Response to L-Asparaginase. Academic Article uri icon

Overview

abstract

  • Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response (ISR) that enables cell survival under nutrient stress. The mechanisms by which ATF4 couples metabolic stresses to specific transcriptional outputs remain unknown. Using functional genomics, we identified transcription factors that regulate the responses to distinct amino acid deprivation conditions. While ATF4 is universally required under amino acid starvation, our screens yielded a transcription factor, Zinc Finger and BTB domain-containing protein 1 (ZBTB1), as uniquely essential under asparagine deprivation. ZBTB1 knockout cells are unable to synthesize asparagine due to reduced expression of asparagine synthetase (ASNS), the enzyme responsible for asparagine synthesis. Mechanistically, ZBTB1 binds to the ASNS promoter and promotes ASNS transcription. Finally, loss of ZBTB1 sensitizes therapy-resistant T cell leukemia cells to L-asparaginase, a chemotherapeutic that depletes serum asparagine. Our work reveals a critical regulator of the nutrient stress response that may be of therapeutic value.

authors

  • Williams, Robert Thomas
  • Guarecuco, Rohiverth
  • Gates, Leah A
  • Barrows, Douglas
  • Passarelli, Maria C
  • Carey, Bryce
  • Baudrier, Lou
  • Jeewajee, Swarna
  • La, Konnor
  • Prizer, Benjamin
  • Malik, Sohail
  • Garcia-Bermudez, Javier
  • Zhu, Xiphias Ge
  • Cantor, Jason
  • Molina, Henrik
  • Carroll, Thomas
  • Roeder, Robert G
  • Abdel-Wahab, Omar
  • Allis, C David
  • Birsoy, Kıvanç

publication date

  • April 7, 2020

Research

keywords

  • Asparagine
  • Aspartate-Ammonia Ligase
  • Leukemia
  • Repressor Proteins

Identity

PubMed Central ID

  • PMC7219601

Scopus Document Identifier

  • 85082778858

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.12.053

PubMed ID

  • 32268116

Additional Document Info

volume

  • 31

issue

  • 4