Alteration of 28S rRNA 2'-O-methylation by etoposide correlates with decreased SMN phosphorylation and reduced Drosha levels.

Marilyn F Burke,Douglas M Mclaurin,Madelyn K Logan,Michael D Hebert

doi:10.1242/bio.041848

Marilyn F Burke, Douglas M Mclaurin + Show 2 more

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https://doi.org/10.1242/bio.041848

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Journal: Biology open	Publication Date: Jan 1, 2019
Citations: 7	License type: CC BY 4.0

Affiliation: University of Mississippi Medical Center

Abstract

ABSTRACTThe most common types of modification in human rRNA are pseudouridylation and 2′-O ribose methylation. These modifications are performed by small nucleolar ribonucleoproteins (snoRNPs) which contain a guide RNA (snoRNA) that base pairs at specific sites within the rRNA to direct the modification. rRNA modifications can vary, generating ribosome heterogeneity. One possible method that can be used to regulate rRNA modifications is by controlling snoRNP activity. RNA fragments derived from some small Cajal body-specific RNAs (scaRNA 2, 9 and 17) may influence snoRNP activity. Most scaRNAs accumulate in the Cajal body – a subnuclear domain – where they participate in the biogenesis of small nuclear RNPs, but scaRNA 2, 9 and 17 generate nucleolus-enriched fragments of unclear function, and we hypothesize that these fragments form regulatory RNPs that impact snoRNP activity and modulate rRNA modifications. Our previous work has shown that SMN, Drosha and various stresses, including etoposide treatment, may alter regulatory RNP formation. Here we demonstrate that etoposide treatment decreases the phosphorylation of SMN, reduces Drosha levels and increases the 2′-O-methylation of two sites within 28S rRNA. These findings further support a role for SMN and Drosha in regulating rRNA modification, possibly by affecting snoRNP or regulatory RNP activity.

Highlights

The major types of modifications in human rRNA are pseudouridylation and 2′-O ribose methylation
We examined if small Cajal body-specific RNAs (scaRNAs), SnoRNPs contain a guide RNA (snoRNA), SMN and Drosha levels were impacted by etoposide
Increased 28S rRNA A2388 and G3923 2′-O-methylation upon etoposide treatment Our previous results have shown that A2388 and G3923 in 28S rRNA and A484 in 18S rRNA may be subjected to regulatory RNPs (regRNPs) control (Burke et al, 2018)

Summary

Introduction

The major types of modifications in human rRNA are pseudouridylation and 2′-O ribose methylation. Human rRNA contains around 100 of each of these modifications, which are performed by small nucleolar ribonucleoproteins (snoRNPs) (Darzacq et al, 2002; Khan and Maden, 1978; Maden et al, 1972; Maden and Salim, 1974; Lafontaine, 2015). SnoRNPs contain a guide RNA (snoRNA) that base pairs at specific sites within the rRNA to direct the modification. There are two kinds of snoRNPs: box H/ACA, which contain dyskerin and are responsible for the pseudouridylation of rRNA, and box C/D, which contain fibrillarin and perform ribosome methylation of rRNA (Kiss, 2004; Baserga et al, 1991; Fatica et al, 2000; Gautier et al, 1997; Schimmang et al, 1989; Szewczak et al, 2002; Tyc and Steitz, 1989; Watkins et al, 1996). Recent work, coupled with advances in the ability to detect pseudouridylation and 2′-O methylation

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