Abstract
ABSTRACTAminoacyl transfer RNA (tRNA) synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNAs, but many of them also perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl tRNA synthetase (PheRS/FARS) levels are elevated in multiple cancers compared to their normal cell counterparts. Our results show that downregulation of PheRS, or only its α-PheRS subunit, reduces organ size, whereas elevated expression of the α-PheRS subunit stimulates cell growth and proliferation. In the wing disc system, this can lead to a 67% increase in cells that stain for a mitotic marker. Clonal analysis of twin spots in the follicle cells of the ovary revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate ∼25% faster than their normal twin cells. This faster growth and proliferation did not affect the size distribution of the proliferating cells. Importantly, this stimulation proliferation turned out to be independent of the β-PheRS subunit and the aminoacylation activity, and it did not visibly stimulate translation.This article has an associated First Person interview with the joint first authors of the paper.
Highlights
Many cancer tissues display higher levels of phenylalanyl transfer RNA synthetase (PheRS; known as FARS) than their healthy counterparts according to the database ‘Gene Expression across Normal and Tumor tissues 2’ (GENT2) (Park et al, 2019)
phenylalanyl transfer RNA (tRNA) synthetase (PheRS) is needed for proliferation and for normal organ and animal growth The Drosophila FARS homolog PheRS is a hetero-tetrameric Aminoacyl tRNA synthetases (aaRSs) consisting of two α- and two β-subunits encoded by α-PheRS and β-PheRS, which are essential genes in Drosophila (Lu et al, 2014)
Our work revealed that PheRS charges transfer RNA (tRNA) with their cognate amino acid Phe, but that it performs a moonlighting function in stimulating cellular growth and proliferation
Summary
Many cancer tissues display higher levels of phenylalanyl transfer RNA (tRNA) synthetase (PheRS; known as FARS) than their healthy counterparts according to the database ‘Gene Expression across Normal and Tumor tissues 2’ (GENT2) (Park et al, 2019). Handling Editor: Ross Cagan Received 29 October 2020; Accepted 21 January 2021 not been studied This might have been due to the assumption that higher PheRS levels could reflect the demand of tumorigenic cells for higher levels of translation, or it could have to do with the difficulty of studying the moonlighting function of a protein that is essential in every cell for basic cellular functions such as translation. Aminoacyl tRNA synthetases (aaRSs) are important enzymes that act by charging tRNAs with their cognate amino acid, a key process for protein translation. This activity makes them essential for accurately translating the genetic information into a polypeptide chain (Schimmel and Söll, 1979). The amino acid-binding site of LysRS has an immune response activity, and TrpRS inhibits vascular endothelial (VE)-cadherin and through this elicits anti-angiogenesis activity (Tzima et al, 2005; Yannay-Cohen et al, 2009)
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