January 2014 – The emerging role of complex modifications of tRNA in signaling pathways

Published: March 4th, 2015

Category: Uncategorized


Coordination of cell growth with nutrient availability, in particular amino acids, is a central problem that has been solved by the implementation of complex regulatory cascades. Although the specific regulatory mechanisms differ between kingdoms and species, a common theme is the use of tRNA molecules as sensors and transducers of amino acid starvation. In many bacteria, amino acid starvation leads to high levels of uncharged tRNAs, a signal for the synthesis of the stringent response’s alarmones, halting transcription of stable RNAs and inducing the synthesis of amino acid synthesis pathways [1]. In gram-positive Bacteria (as well as the Deinococcus-Thermus clade), uncharged tRNAs bind structures (T-boxes) in the leader sequences of mRNA encoding gene, activating the expression of genes involved in amino acid metabolism [2]. In eukaryotes, the conserved General Amino Acid Control (GAAC) response is triggered by shortage of amino acids that leads to the binding of uncharged tRNAs to Gcn2 kinase and, through a cascade of events, to the activation of the central activator of amino acid synthesis genes, Gcn4 [3]. As the study by Scheidt et al. [4]and several other recent studies in this field reveal, variations in charging levels are not the only mechanism by which tRNAs play a role in amino acid starvation responses; levels of post-transcriptional modifications also seem to play major roles.

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Learn more about Dr. Valerie de Crecy-Lagard!

Associate ProfessorDecrecy

Department of Microbiology and Cell Science University of Florida
PhD (1991) University Paris VII (Institut Pasteur), Paris
Post-doctoral (1991-1993) NCI/NIH Bethesda

Contact Information


Teaching Interests

General Microbiology

 Description of Research

General area: Comparative genomic. Bacterial genetics. Experimental evolution. Genetic Code.

The main focus of Dr. de Crecy-Lagard’s laboratory is to utilize the power of microbial genetics to make efficient use of the avalanche of genomic information now available. By combining comparative genomics approaches with experimental verification, new enzymes, pathways and chemistries that had previously evaded identification are revealed.

We have identified several new tRNA modification families that are now under study. By using a new model organism, the naturally transformable bacterium Acinetobacter ADP1, very simple protocols for genetic manipulation have been developed and are now being used to test predictions, build selection strains, and perform pathway engineering. Finally, the use of experimental evolution protocols to adapt bacteria to new metabolic constraints is being explored.

Selected Publications

Yazdani, Mohammad; Zallot, Remi; Tunc-Ozdemir, Meral; de Crecy-Lagard, Valerie; Shintani, David K.;”>Hanson, Andrew D. 2013. Identification of the thiamin salvage enzyme thiazole kinase in Arabidopsis and maize. PHYTOCHEMISTRY (94): 68-73.

Rémi Zallot, Gennaro Agrimi, Claudia Lerma-Ortiz, Howard J. Teresinski, Océane Frelin,Kenneth W. Ellens, Alessandra Castegna, Annamaria Russo, Valérie de Crécy-Lagard, Robert T. Mullen, Ferdinando Palmieri, and Andrew D. Hanson. 2013. Identification of Mitochondrial Coenzyme A Transporters from Maize and Arabidopsis. PLANT PHYSIOLOGY. 162 (2) 581-588

Leonardo Sorci, Ian K. Blaby, Irina A. Rodionova, Jessica De Ingeniis, Sergey Tkachenko, Valérie de Crécy-Lagard and Andrei L. Osterman. 2013. Quinolinate Salvage and Insights for Targeting NAD Biosynthesis in Group A Streptococci JOURNAL OF BACTERIOLOGY 195(4):726-732. 

Ghulam Hasnain, Océane Frelin, Sanja Roje, Kenneth W. Ellens, Kashif Ali, Jiahn-Chou Guan, Timothy J. Garrett, Valérie de Crécy-Lagard, Jesse F. Gregory III, Donald R. McCarty, and Andrew D. Hanson. 2013. Identification and Characterization of the Missing Pyrimidine Reductase in the Plant Riboflavin Biosynthesis Pathway. PLANT PHYSIOLOGY. (161) 48-56.

de Crecy-Lagard, Valerie; Phillips, Gabriela; Grochowski; El Yacoubi, Basma; Jenney, Francis; Adams, Michael W.W.; Murzin, Alexey G.; White, Robert H. 2012. Comparative Genomics Guided Discovery of Two Missing Archaeal Enzyme Families Involved in the Biosynthesis of the Pterin Moiety of Tetrahydromethanopterin and Tetrahydrofolate. ACS CHEMICAL BIOLOGY. 7 (11) 1807-1816.

Valérie de Crécy-Lagard, Farhad Forouhar, Céline Brochier-Armanet, Liang Tong, and John F Hunt. 2012. Comparative genomic analysis of the DUF71/ COG2102 family predicts roles in diphthamide biosynthesis and B12 salvage. BIOLOGY DIRECT. 7:32

Chikwana, Vimbai M.; Stec, Boguslaw; Lee, Bobby W. K.; et al. Structural Basis of Biological Nitrile Reduction. JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 287 Issue: 36 Pages: 30560-30570 Published: AUG 31 2012

Naor, Adit; Thiaville, Patrick C.; Altman-Price, Neta; et al. A Genetic Investigation of the KEOPS Complex in Halophilic Archaea PLOS ONE Volume: 7 Issue: 8 Article Number: e43013 Published: AUG 23 2012

Deutsch, Christopher; El Yacoubi, Basma; de Crecy-Lagard, Valerie; et al. Biosynthesis of Threonylcarbamoyl Adenosine (t(6)A), a Universal tRNA Nucleoside. JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 287 Issue: 17 Pages: 13666-13673 Published: APR 20 2012

By: Chatterjee, Kunal; Blaby, Ian K.; Thiaville, Patrick C.; et al. The archaeal COG1901/DUF358 SPOUT-methyltransferase members, together with pseudouridine synthase Pus10, catalyze the formation of 1-methylpseudouridine at position 54 of tRNA. RNA-A PUBLICATION OF THE RNA SOCIETY Volume: 18 Issue: 3 Pages: 421-433 Published: MAR 2012

Diversity of Archaeosine Synthesis in Crenarchaeota
Phillips, Gabriela; Swairjo, Manal A.; Gaston, Kirk W.; et al. ACS CHEMICAL BIOLOGY Volume: 7 Issue: 2 Pages: 299-304 Published: FEB 2012

YeiR: a metal-binding GTPase from Escherichia coli involved in metal homeostasis
By: Blaby-Haas, Crysten E.; Flood, Jessica A.; de Crecy-Lagard, Valerie; et al. METALLOMICS Volume: 4 Issue: 5 Pages: 488-497 Published: 2012

Functional Promiscuity of the COG0720 Family
By: Phillips, Gabriela; Grochowski, Laura L.; Bonnett, Shilah; et al. ACS CHEMICAL BIOLOGY Volume: 7 Issue: 1 Pages: 197-209 Published: JAN 2012

Experimental Evolution of a Facultative Thermophile from a Mesophilic Ancestor
By: Blaby, Ian K.; Lyons, Benjamin J.; Wroclawska-Hughes, Ewa; et al. APPLIED AND ENVIRONMENTAL MICROBIOLOGY  Volume: 78 Issue: 1 Pages: 144-155 Published: JAN 2012

A 5-formyltetrahydrofolate cycloligase paralog from all domains of life: comparative genomic and experimental evidence for a cryptic role in thiamin metabolism
By: Pribat, Anne; Blaby, Ian K.; Lara-Nunez, Aurora; et al. FUNCTIONAL & INTEGRATIVE GENOMICS  Volume: 11 Issue: 3 Pages: 467-478 Published: SEP 2011

Gcn4 misregulation reveals a direct role for the evolutionary conserved EKC/KEOPS in the t(6)A modification of tRNAs
By: Daugeron, Marie-Claire; Lenstra, Tineke L.; Frizzarin, Martina; et al. NUCLEIC ACIDS RESEARCH  Volume: 39 Issue: 14 Pages: 6148-6160 Published: AUG 2011

Pseudouridine formation in archaeal RNAs: The case of Haloferax volcanii
By: Blaby, Ian K.; Majumder, Mrinmoyee; Chatterjee, Kunal; et al. RNA-A PUBLICATION OF THE RNA SOCIETY  Volume: 17 Issue: 7 Pages: 1367-1380 Published: JUL 2011

Synergistic use of plant-prokaryote comparative genomics for functional annotations
By: Gerdes, Svetlana; El Yacoubi, Basma; Bailly, Marc; et al. BMC GENOMICS Volume: 12 Supplement: 1 Article Number: S2 Published: JUN 15 2011

A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification
By: El Yacoubi, Basma; Hatin, Isabelle; Deutsch, Christopher; et al. EMBO JOURNAL Volume: 30 Issue: 5 Pages: 882-893 Published: MAR 2 2011

Role of a Zn-independent DksA in Zn homeostasis and stringent response
By: Blaby-Haas, Crysten E.; Furman, Ran; Rodionov, Dmitry A.; et al
MOLECULAR MICROBIOLOGY Volume: 79 Issue: 3 Pages: 700-715 Published: FEB 2011

Moonlighting Glutamate Formiminotransferases Can Functionally Replace 5-Formyltetrahydrofolate Cycloligase
By: Jeanguenin, Linda; Lara-Nunez, Aurora; Pribat, Anne; et al.
JOURNAL OF BIOLOGICAL CHEMISTRY  Volume: 285 Issue: 53 Pages: 41557-41566 Published: DEC 31 2010

SOLiD sequencing of four Vibrio vulnificus genomes enables comparative genomic analysis and identification of candidate clade-specific virulence genes
By: Gulig, Paul A.; de Crecy-Lagard, Valerie; Wright, Anita C.; et al. BMC GENOMICS  Volume: 11 Article Number: 512 Published: SEP 24 2010

Biosynthesis of Wyosine Derivatives in tRNA: An Ancient and Highly Diverse Pathway in Archaea
By: de Crecy-Lagard, Valerie; Brochier-Armanet, Celine; Urbonavicius, Jaunius; et al.MOLECULAR BIOLOGY AND EVOLUTION  Volume: 27 Issue: 9 Pages: 2062-2077 Published: SEP 2010

Waller, JC; Alvarez, S; Naponelli, V; Lara-Nunez, A; Blaby, IK; Da Silva, V; Ziemak, MJ; Vickers, TJ; Beverley, SM; Edison, AS; Rocca, JR; Gregory, JF; de Crecy-Lagard, V; Hanson, AD. 2010. A role for tetrahydrofolates in the metabolism of iron-sulfur clusters in all domains of life. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (23): 10412-10417.

Phillips, G; Chikwana, VM; Maxwell, A; El-Yacoubi, B; Swairjo, MA; Iwata-Reuyl, D; de Crecy-Lagard, V. 2010. Discovery and Characterization of an Amidinotransferase Involved in the Modification of Archaeal tRNA. JOURNAL OF BIOLOGICAL CHEMISTRY 285 (17): 12706-12713.

Grosjean, H; de Crecy-Lagard, V; Marck, C. 2010. Deciphering synonymous codons in the three domains of life: Co-evolution with specific tRNA modification enzymes. FEBS LETTERS 584 (2): 252-264

Hyde, JE; Dittrich, S; Wang, P; Sims, PFG; de Crecy-Lagard, V; Hanson, AD. 2008. Plasmodium falciparum: a paradigm for alternative folate biosynthesis in diverse microorganisms?. TRENDS IN PARASITOLOGY 24 (11): 502-508

El Yacoubi, B; Lyons, B; Cruz, Y; Reddy, R; Nordin, B; Agnelli, F; Williamson, JR; Schimmel, P; Swairjo, MA; de Crecy-Lagard, V. 2009. The universal YrdC/Sua5 family is required for the formation of threonylcarbamoyladenosine in tRNA. NUCLEIC ACIDS RESEARCH 37 (9): 2894-2909

Sankaran, B; Bonnett, SA; Shah, K; Gabriel, S; Reddy, R; Schimmel, P; Rodionov, DA; de Crecy-Lagard, V; Helmann, JD; Iwata-Reuyl, D; Swairjo, MA. 2009. Zinc-Independent Folate Biosynthesis: Genetic, Biochemical, and Structural Investigations Reveal New Metal Dependence for GTP Cyclohydrolase IB. JOURNAL OF BACTERIOLOGY 191 (22): 6936-6949

Haas, CE; Rodionov, DA; Kropat, J; Malasarn, D; Merchant, SS; de Crecy-Lagard, V. 2009. A subset of the diverse COG0523 family of putative metal chaperones is linked to zinc homeostasis in all kingdoms of life. BMC GENOMICS 10: art. no.-470

Pribat, A; Blaby, IK; Lara-Nunez, A; Gregory, JF; de Crecy-Lagard, V; Hanson, AD. 2010. FolX and FolM Are Essential for Tetrahydromonapterin Synthesis in Escherichia coli and Pseudomonas aeruginosa. JOURNAL OF BACTERIOLOGY 192 (2): 475-482

Bailly, M; de Crecy-Lagard, V. 2010. Predicting the pathway involved in post-translational modification of Elongation factor P in a subset of bacterial species. BIOLOGY DIRECT 5: art. no.-3

Hanson, AD; Pribat, A; Waller, JC; de Crecy-Lagard, V. 2010. ‘Unknown’ proteins and ‘orphan’ enzymes: the missing half of the engineering parts list – and how to find it. BIOCHEMICAL JOURNAL 425: 1-11, Part 1

Waas, W. F.; de Crécy-Lagard, V.; Schimmel, P., Discovery of a gene family critical to wyosine base formation in a subset of phenylalanine-specific transfer RNAs. J Biol Chem 2005, 280, (45), 37616-22.

Overbeek, R.; Begley, T.; Butler, R. M.; Choudhuri, J. V.; Chuang, H. Y.; Cohoon, M.; de Crecy-Lagard, V. and coll. The subsystems approach to genome annotation and its use in the project to annotate 1000 genomes. Nucleic Acids Res 2005, 33, (17), 5691-702.

Reader JS, Ordoukhanian PT, Kim JG, V. de Crécy-Lagard,, Hwang I, Farrand S, Schimmel P. Major biocontrol of plant tumors targets tRNA synthetase. Science. 2005 Sep 2;309(5740):1533.

Swairjo, M. A.; Reddy, R. P.; Lee, B.; Van Lanen, S. G.; Brown, A.; de Crécy Lagard, V.; Iwata_Reuyl, D.; Schimmel, P., Crystallization and preliminary X-ray characterization of the nitrile reductase QueF- a queuosine biosynthesis enzyme. Acta Crystallogr D Biol Crystallogr 2005, F61, 945-948.

Cirz R. T., J. K. Chin, D. R. Andes, V. de Crécy-Lagard, W. A. Craig and F. Romesberg (2005). Inhibition of mutation and combating antibiotic resistance. PLOS Biology. 3(6):e176. Epub 2005 May 10.

Van Lanen S., Reader J., Swairjo M., V. de Crécy-Lagard and D. Iwata-Reuyl. (2005). From cyclohydrolase to oxido-reductase:evolution of a new enzyme activity from a novel fold. Proc. Natl. Acad. Sci. U S A. 102:4264-9.

Bacher J., V. de Crécy-Lagard and P. Schimmel. (2005). Inhibited cell growth and protein functional changes from an editing deficient tRNA-synthetase. Proc. Natl. Acad. Sci. U S A 102:1697-701.

Grosjean H., de Crécy-Lagard V., and G. R. Björk. (2004) Aminoacylation of the anticodon stem by a tRNA-synthetase paralog: relic of an ancient code? Trends Biochem Sci. 10:519-22.

Metzgar D., Bacher J., Pezo V., Reader, J, Döring V., Schimmel P., Marlière P., and V. de Crécy-Lagard (2004). Acinetobacter so. ADP1: an optimal model organism for genetic analysis and genome engineering Nuc. Acids Res. 32:5780-90.

Hendrickson T. L. H., V. de Crécy-Lagard and P. Schimmel. (2004). Incorporation of non natural amino acids into proteins. Annu. Rev. Biochem. 73:147-176.

Pezo V., Metzgar D., Hendrickson T. L. H. , Waas W. F., Hazebrouck S.,, Döring V., Marlière P., Schimmel P. and V. de Crécy-Lagard. (2004). An Artificially Ambiguous Genetic Code that Confers a Yield Advantage. Proc. Natl. Acad. Sci. U S A. 101:8593-7.

Reader J., Metzgar D., Schimmel P. and V. de Crécy-Lagard. (2004). Identification of four genes necessary for biosynthesis of the modified nucleoside Queuosine. J. Biol. Chem 279(8):6280-5

De Crécy-Lagard V. Finding missing tRNA modification genes: a comparative genomics goldmine. (2004) in “Practical Bioinformatics” edited by J. Bujnicki at Springer-Verlag

Nangle L. T. L., V. de Crécy-Lagard, V. Döring, P. Schimmel, (2002). Genetic code ambiguity: cell toxicity correlated with severity of editing defects in mutant tRNA synthetases. J Biol Chem. 277:45729-45733

Bishop AC, Xu J, Johnson RC, Schimmel P, de Crécy-Lagard V. (2002). Identification of the tRNA-dihydrouridine synthase family. J Biol Chem. 277:25090-25095.

Daugherty M, Polanuyer B, Farrell M, Scholle M, Lykidis A, de Crécy-Lagard V, and A Osterman. (2002). Human Coenzyme A Biosynthesis: Complete Pathway Reconstitution Via Comparative Genomics. J. Biol. Chem. 277:21431-21439.

Hendrickson TL, TK Nomanbhoy, V. de Crécy-Lagard and P. Schimmel. (2002) Direct Evidence for Pre-transfer Hydrolysis of Non-Cognate Substrates by an Aminoacyl-tRNA Synthetase. Molecular Cell. 9:353-362

De Crécy-Lagard V., J. Bellalou, M. Bouzon, R. Mutzel and P. Marlière. (2001) Long term adaptation of a microbial population to a permanent metabolic constraint: overcoming thymineless death by experimental evolution of Escherichia coli. BMC Biotechnol. 1:10.

C. Fàbrega , M. Farrow B. Mukhopadhay, V. de Crécy-Lagard., A. R. Ortiz and P. Schimmel. (2001) A new aminoacyl tRNA synthetase from Archaea that fits into neither of the two known classes. Nature. 411:110-4.

Döring V., H. D. Mootz, L. A. Nangle, T. L. Hendrickson, V. de Crécy-Lagard, P. Schimmel, and Philippe Marlière. (2001) Enlarging the Amino Acid Set of Escherichia coli by Infiltration of the Valine Coding Pathway. Science. 292:501-4.

De Crécy-Lagard V. (1999) Catalysis of amide and ester bond formation by peptide synthetase multienzymatic complexes. Comprehensive Natural Products Chemistry. Eds D. Barton and K. Nakanishi Volume 4: Amino acids, peptides, porphyrins and alkaloids. p.221-238.

De Crécy-Lagard V., P. Servant, C. Granvalet and P. Mazodier. (1999). Alteration of the synthesis of the Clp ATP-dependent protease affects morphological and physiological differentiation in Streptomyces. Mol. Microbiol. 32: 505-518.

Granvalet C, de Crécy-Lagard V. P. Mazodier. (1999). The ClpB ATPase of Streptomyces albus G belongs to the HspR regulon. Mol. Microbiol. 31:521-532

De Crécy-Lagard V., W. Saurin, D. Thibaut, P. Gil, L. Naudin, J. Crouzet and V. Blanc. (1997) Biosynthesis of Pristininamycin I (PI) in Streptomyces pristinaespiralis : molecular characterization of the last structural gene snbD. Antimicrobiol. Chem. Ag. 41:1904-1905

De Crécy-Lagard V., V. Blanc, P. Gill, L. Naudin, P. Didier, D. Bisch, F. Blanche, D. Thibaut and J. Crouzet.(1997) Biosynthesis of Pristininamycin I (PI) in Streptomyces pristinaespiralis : molecular characterization of the first two structural genes snbA and snbC. J. Bacteriol. 179:705-713.

De Crécy-Lagard V., Marlière P.and Saurin W. (1995) Multienzymatic non ribosomal peptide biosynthesis : identification of the functional domains catalysing peptide elongation and epimerisation. C. R. Acad. Sci. III. 318: 927-936.

De Crécy-Lagard V., Binet M. and Danchin A.(1995) Phosphotransferase system of Xanthomonas campestrispv. campestris. : characterization of the fruB gene. Microbiology. 141: 2253-2260.

Gottesman S., Clark W. P., de Crécy-Lagard V. and Maurizi M. (1993). ClpX an alternative subunit for the ATP-dependent Clp protease of Escherichia coli: sequence and in vivo activities. J. Biol. Chem. 268 : 22618-22626.

De Crécy-Lagard V., Bouvet O. M. M., Lejeune P. and Danchin A. (1991). Fructose catabolism in Xanthomonas campestris pv. campestris. J. Biol. Chem. 26 : 18154-18161.

De Crécy-Lagard V., Lejeune P., Bouvet O. M. M. and Danchin A. (1991). Identification of two fructose permeation and phosphorylation pathways in Xanthomonas campestris pv. campestris. Mol. Gen. Genet. 227: 465-472.

De Crécy-Lagard V.Xanthomonas campestris pv. campestris protein similar to catabolite activation factor is involved in regulation of phytopathogenicity. 172 : 5877-5883.


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