Aminoacyl-tRNA synthetases: a family of expanding functions. Mittelwihr, France, October 10-15, 1999.

Abstract

The aminoacyl‐tRNA synthetases (aaRSs) are a family of enzymes well known for their role in protein synthesis. More recent investigations have discovered that this classic family of enzymes is actually capable of a broad repertoire of functions that not only impact protein synthesis, but also extend to a number of other critical cellular activities (Figure 1; Martinis et al ., 1999). Specific aaRSs play roles in cellular fidelity, tRNA processing, RNA splicing, RNA trafficking, apoptosis and transcriptional and translational regulation. A recent EMBO workshop entitled Structure and Function of Aminoacyl‐tRNA Synthetases (Mittelwihr, France, October 10–15, 1998) highlighted the diversity of the aaRSs' role within the cell. These novel activities, as well as significant advances in delineating mechanisms of substrate specificity and the aminoacylation reaction, affirm the family of aaRSs as pharmaceutical targets. Herein we report major advances in the field during the short period since the last aaRS meeting (Francklyn et al ., 1997). Figure 1. Cellular roles and functions of aaRS. Particular aaRSs involved in each of the represented activities are indicated by the three letter code of the amino acid that they activate. ### aaRSs perform dual and essential roles in the cell Eukaryotic pre‐tRNAs are synthesized in the nucleus and require extensive processing to yield functional tRNAs. An elegant series of experiments clearly show that mature tRNAs are charged in the nucleus prior to export to the cytoplasm (Lund and Dahlberg, 1998). Blockage of the tRNA export machinery results in accumulation of nuclear charged tRNAs. Introduction of specific aaRS inhibitors decreases export of the relevant uncharged tRNA. This nuclear aaRS‐dependent aminoacylation reaction was proposed to serve as a stringent quality control mechanism prior to export of mature tRNA to the cytoplasm where it is required for protein synthesis. Nuclear aminoacylation of tRNAs (Arts et al ., 1998; Lund and Dahlberg, 1998) presumably requires import of aaRSs from the cytoplasm. …