Identification of additional regulatory RNPs that impact rRNA and U6 snRNA methylation.

Marilyn F Burke,Madelyn K Logan,Michael D Hebert

doi:10.1242/bio.036095

Abstract

ABSTRACTRibosomes can be heterogeneous, and the major contributor to ribosome heterogeneity is variation in rRNA modification. There are two major types of rRNA modification, pseudouridylation and ribose methylation. In humans, the majority of these rRNA modifications are conducted by two classes of small nucleolar ribonucleoproteins (snoRNPs), which contain a guide RNA (small nucleolar RNA, snoRNA) complexed with proteins. Box H/ACA snoRNPs conduct pseudouridylation modifications and box C/D snoRNPs generate ribose methylation modifications. It is unclear how ribosome heterogeneity is accomplished in regards to the understanding of the signals and factors that regulate rRNA modifications. We have recently reported that a new class of RNP, that we term regulatory RNP (regRNP), may contribute to rRNA modification as well as the modification of nucleolar trafficked U6 snRNA, via interactions with snoRNPs. Here we report the identification of additional regRNP activities that influence the methylation of two sites within 18S rRNA, two sites within 28S rRNA and one site within U6 snRNA. These findings provide additional proof that regulation of snoRNP activity contributes to ribosome heterogeneity.

Highlights

An exciting emerging concept is that of ribosome heterogeneity, leading to specialized ribosomes
When considering all the major spliceosomal snRNAs (U1, U2, U4, U5 and U6), only the RNA polymerase III-derived U6 snRNA has a clear nucleolar biogenesis step (Kiss, 2004). The function of these nucleolar-enriched fragments derived from scaRNA 2, 9 and 17 is, not clear, but we have recently reported the possibility that they may form regulatory RNPs that regulate ribosomal RNA (rRNA) modification by influencing snoRNP activity (Poole et al, 2017)
We hypothesize that these nucleolar enriched fragments form regulatory RNPs that impact rRNA modification by interacting with snoRNPs (Poole et al, 2017)

Summary

Introduction

An exciting emerging concept is that of ribosome heterogeneity, leading to specialized ribosomes. The importance of ribosome heterogeneity leading to specialized ribosomes has recently been demonstrated as a major contributor to tumorigenesis (Marcel et al, 2015; Marcel et al, 2013; Truitt and Ruggero, 2016) These studies found that the reduction of p53 (a common mutation in cancer cells) results in specialized ribosomes with a lower fidelity (i.e. stop codons are bypassed) and a greater likelihood to initiate translation through internal ribosome entry sequences (IRESs) (Belin et al, 2009; Marcel et al, 2015; Marcel et al, 2013). Reduction of p53 results in the increased translation of IRES-containing messages whose products (such as IGF-1R, c-myc, VEGF-A and FGF1) promote tumor development (Marcel et al, 2015)

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