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

Abstract

Edited by Karin Musier-Forsyth 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 transacting 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 transacting 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.

YARS as an oncogenic protein that promotes gastric cancer progression through activating PI3K-Akt signaling

“…Thus, it is reasonable to believe that besides combing PI3K-Akt inhibitors (Konstantinopoulos Several studies have also addressed aaRS's association with regulative pathways and processes. A predictive work raised the potential interaction between aaRSs (including LRS, DRS, RRS, IRS, KRS, QRS, EPRS) and MAPK/ PI3K-Akt pathways (Hyeon et al 2019). YARS was reported directly interacting with TRIM28/HDAC1 and sequestering HDAC1-mediated deacetylation on E2F1, thus enhances E2F1-mediated upregulation of homologous recombination (HR) factors and provides protection against DNA damage (Wei et al 2014).…”

“…On the other hand, the upregulation of aaRSs, including YARS, was observed in several types of cancer (Guo et al 2010;Hsu et al 2019), while polymorphisms in aaRS genes were reported to be associated with breast cancer risk (He et al 2015). Emerging studies also implicated the involvement of aaRSs with multiple pathway networks through constituting the multi-tRNA synthetase complex (MSC) (Hyeon et al 2019) and raised the possibility of aminoacyl-tRNA synthetases as therapeutic targets against autoimmune diseases, rare diseases, and even cancer (Kwon et al 2019). Nevertheless, although abundantly exists and functions in all organisms, YARS's actual linkage with cancer remains unspecified.…”

Aminoacyl-tRNA synthetases

“…For example, it is known that AIMP3, which is specifically bound to MRS, relays the methionylated initiator tRNA to the initiator complex (Kang et al 2012). One aspect that is fundamentally clear is that in addition to the canonical tRNA charging activity, the MSC components are involved in several fundamental processes outside of translation such as transcription, cell-signaling and tumorigenesis (Hyeon et al 2019). For example, it has been shown that LeuRS interacts with the Target of Rapamycin (TOR) pathway, a highly conserved metabolic pathway involved in regulation of several key processes such as energy metabolism, protein synthesis, nutrient uptake or autophagy.…”

3-Dimensional architecture of the human multi-tRNA synthetase complex

“…The molecular size of the MSC, ∼1.0–1.2 MDa ( 14 , 22 , 25 , 26 ), is less than the ∼2 MDa, 60S eukaryotic large ribosomal subunit, however, given that RNA comprises at least half of the ribosome mass, the protein mass of the MSC is comparable to that of the 60S ribosome. Based on stoichiometric studies of the purified complex, and structural studies of purified constituents, the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure 1B , adapted from ( 27 , 28 )). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers ( 20 ).…”