Evolution of the multi-tRNA synthetase complex and its role in cancer

Do Young Hyeon,Jong Hyun Kim,Tae Jin Ahn,Yeshin Cho,Daehee Hwang,Sunghoon Kim

doi:10.1074/jbc.rev118.002958

Abstract

Aminoacyl-tRNA synthetases (ARSs) are enzymes that ligate their cognate amino acids to tRNAs for protein synthesis. However, recent studies have shown that their functions are expanded beyond protein synthesis through the interactions with diverse cellular factors. In this review, we discuss how ARSs have evolved to expand and control their functions by forming protein assemblies. We particularly focus on a macromolecular ARS complex in eukaryotes, named multi-tRNA synthetase complex (MSC), which is proposed to provide a channel through which tRNAs reach bound ARSs to receive their cognate amino acid and transit further to the translation machinery. Approximately half of the ARSs assemble into the MSC through cis-acting noncatalytic domains attached to their catalytic domains and trans-acting factors. Evolution of the MSC included its functional expansion, during which the MSC interaction network was augmented by additional cellular pathways present in higher eukaryotes. We also discuss MSC components that could be functionally involved in the pathophysiology of tumorigenesis. For example, the activities of some trans-acting factors have tumor-suppressing effects or maintain DNA integrity and are functionally compromised in cancer. On the basis of Gene Ontology analyses, we propose that the regulatory activities of the MSC-associated ARSs mainly converge on five biological processes, including mammalian target of rapamycin (mTOR) and DNA repair pathways. Future studies are needed to investigate how the MSC-associated and free-ARSs interact with each other and other factors in the control of multiple cellular pathways, and how aberrant or disrupted interactions in the MSC can cause disease.

Highlights

Aminoacyl-tRNA synthetases (ARSs) are enzymes that ligate their cognate amino acids to tRNAs for protein synthesis
Of multiple cellular pathways, and how aberrant or disrupted interactions in the multitRNA synthetase complex (MSC) can cause disease. In light of their integral catalytic roles that link the genetic code to protein [1,2,3], aminoacyl-tRNA synthetases (ARSs)5 are thought to have ancient origins and to have evolved to meet the demands of accurate protein synthesis and complex system development
Eukaryotic ARSs fall into two groups based on their capability to associate with a multi-tRNA synthetase complex (MSC) or to remain free [7, 8]

Summary

Formation of the MSC

Several ARSs assemble to form the MSC through cis-acting noncatalytic domains attached to their catalytic domains as well as the three trans-acting factors, AIMP1, AIMP2, and AIMP3 [22,23,24,25,26]. Among trans-acting factors, AIMP2 appears to serve as a critical nucleation factor, mediating multiple interactions with many ARS components [27, 28] For this reason, depletion of AIMP2 triggers a massive disintegration of the MSC [22]. AIMP3 and MRS are connected through their GST-homology domains (Fig. 1B, right) [17] This complex is further extended to form a stable heterotetramer with the GST-homology domains embedded in EPRS and AIMP2 [17]. These subcomplexes are further connected to form the whole MSC (Fig. 1C). Elucidation of the detailed mechanisms for the delivery of tRNAs and amino acids awaits further in-depth analysis

Pathophysiological implications of the MSC in cancer

Comparison of ARS networks among different species

Functional expansion of the MSC throughout evolution

Implications of the MSC in mTOR signaling and DNA repair

Findings

ARS and disease