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CTP sensing and Mec1ATR-Rad53CHK1/CHK2 mediate a two-layered response to inhibition of glutamine metabolism.

Authors :
Ajazi, Arta
Choudhary, Ramveer
Tronci, Laura
Bachi, Angela
Bruhn, Christopher
Source :
PLoS Genetics; 3/3/2022, Vol. 18 Issue 3, p1-30, 30p
Publication Year :
2022

Abstract

Glutamine analogs are potent suppressors of general glutamine metabolism with anti-cancer activity. 6-diazo-5-oxo-L-norleucine (DON) is an orally available glutamine analog which has been recently improved by structural modification for cancer treatment. Here, we explored the chemogenomic landscape of DON sensitivity using budding yeast as model organism. We identify evolutionarily conserved proteins that mediate cell resistance to glutamine analogs, namely Ura8<superscript>CTPS1/2</superscript>, Hpt1<superscript>HPRT1</superscript>, Mec1<superscript>ATR</superscript>, Rad53<superscript>CHK1/CHK2</superscript> and Rtg1. We describe a function of Ura8 as inducible CTP synthase responding to inhibition of glutamine metabolism and propose a model for its regulation by CTP levels and Nrd1-dependent transcription termination at a cryptic unstable transcript. Disruption of the inducible CTP synthase under DON exposure hyper-activates the Mec1-Rad53 DNA damage response (DDR) pathway, which prevents chromosome breakage. Simultaneous inhibition of CTP synthase and Mec1 kinase synergistically sensitizes cells to DON, whereas CTP synthase over-expression hampers DDR mutant sensitivity. Using genome-wide suppressor screening, we identify factors promoting DON-induced CTP depletion (TORC1, glutamine transporter) and DNA breakage in DDR mutants. Together, our results identify CTP regulation and the Mec1-Rad53 DDR axis as key glutamine analog response pathways, and provide a rationale for the combined targeting of glutamine and CTP metabolism in DDR-deficient cancers. Author summary: Cancer cell proliferation is supported by high metabolic activity. Targeting metabolic pathways is therefore a strategy to suppress cancer cell growth and survival. Glutamine is a key metabolite that supports a plethora of anabolic, growth-promoting reactions in the cell. Therefore, the use of small molecules that block glutamine-dependent reactions has been extensively investigated in cancer therapy. Knowledge about the pathways that influence sensitivity towards glutamine metabolism inhibitors would help to tailor the use of such glutamine-targeting therapies. In this study, we use budding yeast as model system to identify the pathways that mediate or restrict the toxicity of a representative inhibitor of glutamine metabolism, the glutamine analog 6-diazo-5-oxo-L-norleucine (DON). We describe a response mechanism mediated by an inducible CTP synthase that promotes nucleotide homeostasis during DON exposure to prevent DNA breaks. Moreover, we show that combined inhibition of the inducible CTP synthase and DNA damage response enhances DON toxicity, pointing out a potential therapeutic application in cancers with defective DNA damage response. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15537390
Volume :
18
Issue :
3
Database :
Complementary Index
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
155553905
Full Text :
https://doi.org/10.1371/journal.pgen.1010101