Elongator Subunit 3 (Elp3) Is Required for Zebrafish Trunk Development

Abstract

Transfer RNAs (tRNAs) are the most post-transcriptionally modified RNA species. Some of these modifications, especially the ones located in the anti-codon loop, are required for decoding capabilities of tRNAs. Such is the case for 5-methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U), synthetized by the Elongator complex. Mutants for its sub-units display pleiotropic phenotypes. In this paper, we analyze the role of elp3 (Elongator catalytic sub-unit) in zebrafish development. We found that it is required for trunk development; elp3 knock-down animals presented diminished levels of mcm5s2U and sonic hedgehog (Shh) signaling activity. Activation of this pathway was sufficient to revert the phenotype caused by elp3 knockdown, indicating a functional relationship between Elongator and Shh through a yet unknown molecular mechanism.

Cryo-EM structures of the human Elongator complex at work

“…In our structures, the KAT domain of human ELP3, which binds the acetyl-CoA ligand, is similar to known Elp3 structures 18 , 19 , 30 and to the crystal structure of the GCN5-type acetyltransferases, which bind and utilize acetyl-CoA to acetylate lysine residues of histones 31 . Our previously reported structures of a bacterial Elp3 homolog demonstrated the structural mechanism by which it coordinates DCA in its active site.…”

How Elongator Acetylates tRNA Bases

“…Impaired Elongator activity causes the codon-dependent mis-production of individual proteins and proteome imbalance, which is detrimental for many fundamental cellular functions [15]. Furthermore, diminished Elp3 expression levels are the cause of spine malformation in zebrafish [34] and Elp3 mutations were identified in a mutagenesis screen for the key players guiding axon formation, synaptic transmission, and neuronal survival in Drosophila development (Figure 3) [35]. Moreover, it was found that amyotrophic lateral sclerosis (ALS) patients express lower levels of Elp3 in their motor cortex, which is accounted for in proteome impairment.…”