Gene- and Species-Specific Hox mRNA Translation by Ribosome Expansion Segments

• Published in: Molecular cell 2020-12, Vol.80 (6), p.980-995.e13
• Main Authors: Leppek, Kathrin, Fujii, Kotaro, Quade, Nick, Susanto, Teodorus Theo, Boehringer, Daniel, Lenarčič, Tea, Xue, Shifeng, Genuth, Naomi R., Ban, Nenad, Barna, Maria
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; ES9S; expansion segment; Gene Expression Regulation - genetics; Genes, Homeobox - genetics; Homeodomain Proteins - genetics; Homeodomain Proteins - ultrastructure; Hox cluster; internal initiation; internal ribosome entry site; mRNA translation; Nucleic Acid Conformation; Protein Biosynthesis - genetics; ribosomal RNA; ribosome; ribosome engineering; Ribosomes - genetics; Ribosomes - ultrastructure; RNA structure; RNA, Messenger - genetics; RNA, Ribosomal - genetics; RNA, Ribosomal - ultrastructure; RNA-protein interaction; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - ultrastructure; Species Specificity; stem-loop; yeast
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.10.023

Ribosomes have been suggested to directly control gene regulation, but regulatory roles for ribosomal RNA (rRNA) remain largely unexplored. Expansion segments (ESs) consist of multitudes of tentacle-like rRNA structures extending from the core ribosome in eukaryotes. ESs are remarkably variable in sequence and size across eukaryotic evolution with largely unknown functions. In characterizing ribosome binding to a regulatory element within a Homeobox (Hox) 5′ UTR, we identify a modular stem-loop within this element that binds to a single ES, ES9S. Engineering chimeric, “humanized” yeast ribosomes for ES9S reveals that an evolutionary change in the sequence of ES9S endows species-specific binding of Hoxa9 mRNA to the ribosome. Genome editing to site-specifically disrupt the Hoxa9-ES9S interaction demonstrates the functional importance for such selective mRNA-rRNA binding in translation control. Together, these studies unravel unexpected gene regulation directly mediated by rRNA and how ribosome evolution drives translation of critical developmental regulators. [Display omitted] •A Hoxa9 5′ UTR stem-loop, P4, selectively binds to the rRNA expansion segment ES9S•“Humanized” ES9S yeast ribosomes reveal species-specific binding of ribosomes to P4•Disrupting Hoxa9-ES9S binding in neural stem cells reduces Hoxa9 mRNA translation•Selective mRNA recruitment via ESs is a novel gene-regulatory role for rRNA Leppek and colleagues describe a novel layer of gene regulation mediated directly by ribosomal RNA (rRNA). They demonstrate that extended regions of rRNA, called expansion segments, which vary in sequence and size across evolution, selectively interact with an RNA stem-loop in the Hoxa9 5′ UTR to guide species- and gene-specific translation.