Novel functions of cytoplasmic aminoacyl-tRNA synthetases shaping the hallmarks of cancer

With the intense protein synthesis demands of cancer, the classical enzymatic role of aminoacyl-tRNA synthetases (aaRSs) is required to sustain tumor growth. However, many if not all aaRSs also possess regulatory functions outside of the domain of catalytic tRNA aminoacylation, which can further contribute to or even antagonize cancers in non-translational ways. These regulatory functions of aaRS are likely to be manipulated in cancer to ensure uncontrolled growth and survival. This review will largely focus on the unique capacities of individual and sometimes collaborating synthetases to influence the hallmarks of cancer, which represent the principles and characteristics of tumorigenesis. An interesting feature of cytoplasmic aaRSs in higher eukaryotes is the formation of a large multi-synthetase complex (MSC) with nine aaRSs held together by three non-enzymatic scaffolding proteins (AIMPs). The MSC-associated aaRSs, when released from the complex in response to certain stimulations, often participate in pathways that promote tumorigenesis. In contrast, the freestanding aaRSs are associated with activities in both directions—some promoting while others inhibiting cancer. The AIMPs have emerged as potent tumor suppressors through their own distinct mechanisms. We propose that the tumor-suppressive roles of AIMPs may also be a consequence of keeping the cancer-promoting aaRSs within the MSC. The rich connections between cancer and the synthetases have inspired the development of innovative cancer treatments that target or take advantage of these novel functions of aaRSs.