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Research > Team Genetics of Metabolic Pathways

Genetics of Metabolic Pathways

Principal Investigator : Bertrand Daignan-Fornier

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Team Members

Johanna Ceschin - ASI UB

Bertrand Daignan-Fornier - DR1 CNRS

José Eduardo Gomes - MCU UB

Roxane Marsac - Doctorante AFM

Michel Moenner - Professeur UB

Benoît Pinson - DR2 CNRS

Christelle Saint-Marc - AI CNRS

 

Research Activity

Cells permanently sense their metabolic status and adequately modulate key cellular functions. This highly integrated process is crucial to adjust interconnected pathways and maintain homeostasis. To achieve this goal, cells use strategic metabolites to sense the metabolome and to modulate gene expression accordingly. By combining genetics to metabolic and biochemical approaches, we aimed at understanding several regulatory mechanisms that involve key signaling metabolites and their protein effectors. We recently identified NAD+ as an important regulator of cell size homeostasis. We also established that two metabolic intermediates of the purine biosynthesis pathway, namely AICAR and SAICAR, represent strategic signaling molecules that co-regulate other metabolic pathways.

 

bdf-fig1Caenorhabditis elegans

 

AICAR is a molecule with multiple promising antiproliferative properties and we are currently identifying cellular functions affected by this metabolite in yeast and mammalian cells. Importantly, AICAR was shown to accumulate in several metabolic rare diseases. We develop animal model of these pathologies using the nematode C. elegans. Our analysis presently focuses on the characterization of adsl-1Δ and atic-1Δ mutants that are deficient for crucial enzymes in the purine biosynthesis pathway.

 

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Human epithelial cells

 

 

Keywords

Purine metabolism - Yeast - Nematode - Cancer cells

 

Selected publications 2009-2018

Albrecht D, Hürlimann HC, Ceschin J, Saint-Marc C, Pinson B, Daignan-Fornier B. Multiple chemo-genetic interactions between a toxic metabolite and the ubiquitin pathway in yeast. Curr Genet. 2018 Dec;64(6):1275-1286

Huyet J, Ozeir M, Burgevin MC, Pinson B, Chesney F, Remy JM, Siddiqi AR, Lupoli R, Pinon G, Saint-Marc C, Gibert JF, Morales R, Ceballos-Picot I, Barouki R, Daignan-Fornier B, Olivier-Bandini A, Augé F, Nioche P. Structural Insights into the Forward and Reverse Enzymatic Reactions in Human Adenine Phosphoribosyltransferase. Cell Chem Biol. 2018 Jun 21;25(6):666-676.e4

Philippe C, Pinson B, Dompierre J, Pantesco V, Viollet B, Daignan-Fornier B, Moenner M. AICAR Antiproliferative Properties Involve the AMPK-Independent Activation of the Tumor Suppressors LATS 1 and 2. Neoplasia. 2018 Jun;20(6):555-562

Bonnot C, Proust H, Pinson B, Colbalchini FP, Lesly-Veillard A, Breuninger H, Champion C, Hetherington AJ, Kelly S, Dolan L. Functional PTB phosphate transporters are present in streptophyte algae and early diverging land plants. New Phytol. 2017 May;214(3):1158-1171

Albrecht D, Ceschin J, Dompierre J, Gueniot F, Pinson B, Daignan-Fornier B. Chemo-Genetic Interactions Between Histone Modification and the Antiproliferation Drug AICAR Are Conserved in Yeast and Humans. Genetics. 2016 Dec;204(4):1447-1460

Bonnot C, Pinson B, Clément M, Bernillon S, Chiarenza S, Kanno S, Kobayashi N, Delannoy E, Nakanishi TM, Nussaume L, Desnos T. A chemical genetic strategy identify the PHOSTIN, a synthetic molecule that triggers phosphate starvation responses in Arabidopsis thaliana. New Phytol. 2016 Jan;209(1):161-76

Ceschin J, Hürlimann HC, Saint-Marc C, Albrecht D, Violo T, Moenner M, Daignan-Fornier B, Pinson B. Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 5-Aminoimidazole-4-carboxamide-1-?-d-ribofuranoside Monophosphate (AICAR). J Biol Chem. 2015 Sep 25;290(39):23947-59

Jabouille A, Delugin M, Pineau R, Dubrac A, Soulet F, Lhomond S, Pallares-Lupon N, Prats H, Bikfalvi A, Chevet E, Touriol C, Moenner M. Glioblastoma invasion and cooption depend on IRE1? endoribonuclease activity. Oncotarget. 2015 Sep 22;6(28):24922-34

Saint-Marc C, Hürlimann HC, Daignan-Fornier B, Pinson B. Serine hydroxymethyltransferase: a key player connecting purine, folate and methionine metabolism in Saccharomyces cerevisiae. Curr Genet. 2015 Nov;61(4):633-40

Tocco A, Pinson B, Thiébaud P, Thézé N, Massé K. Comparative genomic and expression analysis of the adenosine signaling pathway members in Xenopus. Purinergic Signal. 2015 Mar;11(1):59-77

Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J, Groc L, Oliet SH. Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Nat Neurosci. 2015 Feb;18(2):219-26

Ceballos-Picot I, Le Dantec A, Brassier A, Jaïs JP, Ledroit M, Cahu J, Ea HK, Daignan-Fornier B, Pinson B. New biomarkers for early diagnosis of Lesch-Nyhan disease revealed by metabolic analysis on a large cohort of patients. Orphanet J Rare Dis. 2015 Jan 23;10:7

Ceschin J, Saint-Marc C, Laporte J, Labriet A, Philippe C, Moenner M, Daignan-Fornier B, Pinson B. Identification of yeast and human 5-aminoimidazole-4-carboxamide-1-?-d-ribofuranoside (AICAr) transporters. J Biol Chem. 2014 Jun 13;289(24):16844-54

Moretto F, Sagot I, Daignan-Fornier B, Pinson B. A pharmaco-epistasis strategy reveals a new cell size controlling pathway in yeast. Mol Syst Biol. 2013 Nov 12;9:707

Ljungdahl PO, Daignan-Fornier B. Regulation of amino acid, nucleotide, and phosphate metabolism in Saccharomyces cerevisiae. Genetics. 2012 Mar;190(3):885-929

Daignan-Fornier B, Pinson B. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects. Metabolites. 2012 Mar 23;2(2):292-302

Hürlimann HC, Laloo B, Simon-Kayser B, Saint-Marc C, Coulpier F, Lemoine S, Daignan-Fornier B, Pinson B. Physiological and toxic effects of purine intermediate 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR) in yeast. J Biol Chem. 2011 Sep 2;286(35):30994-1002

Saint-Marc C, Pinson B, Coulpier F, Jourdren L, Lisova O, Daignan-Fornier B. Phenotypic consequences of purine nucleotide imbalance in Saccharomyces cerevisiae. Genetics. 2009 Oct;183(2):529-38, 1SI-7SI

Pinson B, Vaur S, Sagot I, Coulpier F, Lemoine S, Daignan-Fornier B. Metabolic intermediates selectively stimulate transcription factor interaction and modulate phosphate and purine pathways. Genes Dev. 2009 Jun 15;23(12):1399-407

 

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Saccharomyces cerevisiae