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Evolution of the Glx-Trna Synthetase Family: the Glutaminyl Enzyme As A

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Evolution of the Glx-Trna Synthetase Family: the Glutaminyl Enzyme As A Proc. Nati. Acad. Sci. USA Vol. 91, pp. 8670-8674, August 1994 Evolution Evolution of the Glx-tRNA synthetase family: The glutaminyl enzyme as a case of horizontal gene transfer (gene duplication/mlecuar phylogeny/am acyl-tRNA synthetase/human cDNA) VALtRIE LAMOURt, SOPHIE QUEVILLONt, SYLVIE DIRIONG§, VAN CONG N'GUYEN§, MARC LIPINSKIt, AND MARC MIRANDE4 tLaboratoire de Biologie des Tumeurs Humaines, Unitd de Recherche Associ6e 1156, and §Laboratoire de Cytog6n6tique et de G6n6tique Oncologiques, Unite de Recherche Associ6e 1158, Centre National de la Recherche Scientifique, Institut Gustave Roussy, 94805 Villejuif Cedex, France; and tLaboratoire d'Enzymologie du Centre National de la Recherche Scientifique, 91190 Gif sur Yvette, France Communicated by Russell F. Doolittle, March 10, 1994 ABSTRACT An important step ensuring the fidelity in in). The prevailing hypothesis assumes that the ancestral protein biosynthesis is the aminocylatlon of tRNAs by ami- organism from which modem bacteria and eukaryotic cells noacyl-tRNA synthetases. The accuracy ofthis process rests on arose contained only GluRS, GlnRS appearing later on, after a family of20 enzymes, one for each amino add. One exception duplication of the GluRS gene (7, 9). is the formation of Gln-tRNAGID that can be accomplished by A cDNA cloned in Drosophila has been shown previously two different pathways: a ylation of tRNAc with Gin to encode a multifunctional protein with GluRS and ProRS by glutaminyl-tRNA synthetase (GInRS; EC 6.1.1.18) or trans- carried by the N and C termini, respectively (10). The amidation of Glu from Glu-tRNACh mischarged by glutamyl- N-terminal domain showed a higher homology with E. coli tRNA synthetase (GluRS; EC 6.1.1.17). The latter pathway is GlnRS (37% ofidentical amino acids) than with E. coli GluRS widespread among bacteria and organelles that, accordingly, (22% identity). However, only GluRS activity was detected lack GliRS. However, some bacterial species, such as Esche- when the corresponding cDNA fragment was expressed in E. rchia coli, do possess a GIuRS activity, which is responsible for coli (10). These observations strengthened the view accord- Gln-tRNACh formation. In the cytoplasm of eukaryotic cells, ing to which Glx-tRNA synthetase genes are closely related both GIuRS and GlnRS activities can be detected. To gain more and diverged recently in evolution. insight into the evolutionary relationship between GluRS and Earlier on, a human cDNA displaying an overall structure GlnRS enzyme species, we have now isolated and characterized similar to that of the fly cDNA encoding the multifunctional a human cDNA encoding GliRS. The deduced amino add protein with glutamyl- and prolyl-tRNA synthetase activities sequence shows a strong similarity with other known GlnRSs (GluProRS) had been reported (11). This cDNA was attrib- and with eukaryotic GluRSs. A molecular phylogenetic anal- uted to a GlnRS cDNA solely on the basis of sequence ysis was conducted on the 14 GlxRS (GhuRS or GInRS) comparison (11). Since the Drosophila and human proteins sequences available to date. Our data suggest that bacterial were strikingly similar (66% of identical residues), we have GlnRS has a eukaryotic origin and was acquired by a mech- proposed that this human cDNA would rather encode a anism of horizontal gene transfer. GluProRS enzyme (10). This implied that human GlnRS remained to be cloned. In this paper, we describe the Aminoacyl-tRNA synthetases define a family of20 enzymes, isolation of a human GlnRS cDNA that has been entirely each specifically responsible for the esterification of a given sequenced. The identification of the actual GlnRS cDNA tRNA by its cognate amino acid (1, 2). All 20 synthetases sheds some light into the evolutionary history of the G1xRS have now been cloned fromEscherichia coli and several from genes. In particular, a molecular phylogeny analysis per- eukaryotic cells. Based on the analysis of their amino acid formed with all GUxRS sequences available to date suggests sequences, and on the crystal structures of 5 enzymes, an evolutionary scenario involving gene duplication of a aminoacyl-tRNA synthetases were partitioned into two dis- eukaryotic GluRS, followed by a lateral gene transfer event. tinct structural classes (3-6). It appears to be a constant rule This scheme is consistent with the presence of GlnRS in that an aminoacyl-tRNA synthetase with a given specificity some, but not all, prokaryotic cells. always belongs to the same class, I or II, irrespective of its prokaryotic or eukaryotic origin. No example ofclass switch- ing has been reported to date. MATERIALS AND METHODS Among the 20 synthetases, a special issue concerns the Isolation and Characterization of Human GIIRS cDNA. An evolutionary relationship between glutamyl-tRNA synthe- inter-Alu clone, DD4, was obtained from a radiation hybrid tase (GluRS; EC 6.1.1.17) and glutaminyl-tRNA synthetase selected for its content in human chromosome 22fragments (12) (GlnRS; EC 6.1.1.18). These two class I synthetases have and used to screen a human fetal brain cDNA library con- very similar primary structures, indicating that GluRS and structed in A-ZAPII vector (Stratagene). The cDD4 pBluescript GlnRS have evolved from a common ancestor (6, 7). In that phagemid obtained was shown to contain a 5-kb-long insert that connection, it is noteworthy that GlnRS is the only synthe- proved to be a chimera. The 5' extremity of cDD4, encoding tase known to be dispensable for protein synthesis. In human GlnRS, was used as a probe to isolate clone F27 from a Gram-positive eubacteria, cyanobacteria and halobacteria, human liver cDNA library made available to us by Pierre as well as in mitochondria and chloroplasts from eukaryotic Meulien (Institut Pasteur-Mdrieux, Marcy-l'Etoile, France). To cells, GluRS aminoacylates both tRNAGlU and tRNAGhn with reconstitute a full-length cDNA, the 5' EcoRI fragment ofF27, glutamate; Gln-tRNA0Gn is formed by transamidation of the containing the translation initiation codon, was subcloned into misacylated Glu-tRNAG'n (refs. 8 and 9 and references there- Abbreviations: GhnRS, glutaminyl-tRNA synthetase; GluRS, glu- The publication costs of this article were defrayed in part by page charge tamyl-tRNA synthetase; GluProRS, multifunctional protein with payment. This article must therefore be hereby marked "advertisement" glutamyl- and prolyl-tRNA synthetase activities; IPTG, isopropyl in accordance with 18 U.S.C. §1734 solely to indicate this fact. 3-D-thiogalactoside. 8670 Evolution:Evolution:LamourLamouretetal.al.~~~~Proc.Nati. Acad. Sci. USA 91 (1994) 8671 pffluescript II SK(+) to give F27.6. The Eag I-Eco47Ill 5' during a search for new genes mapping to a disease- fr-agment of cDD4 was then replaced with the corresponding associated region of human chromosome 22. Whereas the 3' fr~agment isolated from F27.6. The entire sequence of G~nRS end of that cDNA was found to map to the expected region cDNA was established on both strands by automated sequenc- of chromosome 22, the 5' end did not. Partial sequencing of ing (Applied Biosystems, model 373A) using fluorescent prim- cDD4 suggested that this cDNA must be a chimera. The ers or fluorescent dideoxynucleotides in combination with amino acid sequences deduced from its 5' moiety were custom-designed primers (Bioprobe, Montreuil-sous-Bois, closely homologous to the GlnRS sequences stored in protein France). data bases. Chromosomal Asigmet.Somatic cell hybrids used to chro- The cDNA from cDD4 did not code for the 53 N-terminal mosomally assign the human GlnRS gene have been described residues of GlnRS (Fig. 1). The 5' upstream sequences were (13). Southern blots of HindIII-digested genomic, DNA from obtained by screening a human liver library with a probe these hybrids were hybridized with a nick-translated GlnRS corresponding to the 5' end of cDD4. The 2437-bp-long cDNA probe, encompassing amino acids 54-553 in Fig. 1. The cDNA sequence (EMBL data library, accession no. X76013) aminoacylase 1 gene (ACY1) that maps to chromosome 3p21 an open fr-ame of2325 nucleotides. The ATG was used as a displays reading reference chromosome 3 marker (14). initiation codon is preceded by 5 nucleotides defining a Western Blot Analysis and Activity Measurements. A frag- suitable translation initiation site The 3' ment of for amino acids 165-775 in was (23). 107-bp-long cDD4, coding Fig. 1, untranslated region contains a short poly(A) tail preceded by cloned in the pGEX-3X vector (Pharmacia). The expression a canonical AATAAA of the fusion was induced polyadenylylation signal. By Northern protein by isopropyl f3-D- blot on RNA Extracts were either analysis total isolated from various tumor cell thiogalactoside (I]PTG). prepared by a mRNA of ==2500 nucleotides was observed sonication ofa bacterial suspension (sonicated extracts) or by lines, single (not SDS treatment of the bacterial pellet (total extract), followed shown). by centrifugation to remove insoluble material. Aminoacyl- Chromosomal Assignment. The gene encoding the human tRNA synthetase activities present in the sonicated extracts GlnRS was mapped to chromosome 3 by hybridization of a of recombinant bacteria were assayed by the aminoacylation GlnRS probe to a panel of 25 somatic cell hybrids (13). A reaction (15), using beef liver tRNA and 14C-labeled amino correlation was observed between the detection of a human- acids (Amersham). Sonicated and total extracts were sub- specific GlnRS signal and the presence of human chromo- jected to Western blot analysis (16), using antibodies directed some 3 in the hybrid. Whereas 14 of the 15 GlnRS-positive to the aminoacyl-tRNA synthetase components of the sheep hybrids were found to contain human chromosome 3, no liver complex (17) and the ECL detection reagents from chromosome 3 was detected in any of the 10 GlnRS-negative Amersham. hybrids (not shown). The single hybrid that was GhiRS- In Vitro Tra~nslation. The reconstituted fulfl-length GirnRS positive but did not contain an intact chromosome 3, as cDNA was transcribed in vitro using the riboprobe Gemini II assessed by cytogenetic analysis, nevertheless scored posi- system (Promega).
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