The Conserved RNA Exonuclease Rexo5 Is Required for 3′ End Maturation of 28S rRNA, 5S rRNA, and snoRNAs

Stefanie Gerstberger,Cindy Meyer,Sigi Benjamin-Hong,Joe Rodriguez,Daniel Briskin,Claudia Bognanni,Kimberly Bogardus,Hermann Steller,Thomas Tuschl

doi:10.1016/j.celrep.2017.09.067

Stefanie Gerstberger, Cindy Meyer + Show 7 more

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Non-coding RNA biogenesis in higher eukaryotes has not been fully characterized. Here, we studied the Drosophila melanogaster Rexo5 (CG8368) protein, a metazoan-specific member of the DEDDh 3'-5' single-stranded RNA exonucleases, by genetic, biochemical, and RNA-sequencing approaches. Rexo5 is required for small nucleolar RNA (snoRNA)and rRNA biogenesis and is essential in D.melanogaster. Loss-of-function mutants accumulate improperly 3' end-trimmed 28S rRNA, 5S rRNA, and snoRNA precursors invivo. Rexo5 is ubiquitously expressed at low levels in somatic metazoan cells but extremely elevated in male and female germ cells. Loss of Rexo5 leads to increased nucleolar size, genomic instability, defective ribosome subunit export, and larval death. Loss of germline expression compromises gonadal growth and meiotic entry during germline development.

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Ribosome biogenesis is central to protein synthesis and perhaps the most complex RNA metabolic process in eukaryotic cells, involving more than 200 ribosomal proteins and assembly factors in Saccharomyces cerevisiae and over 400 in human cells (Lafontaine, 2015; Tafforeau et al, 2013)
A subset of small nucleolar RNA (snoRNA), including U3 and the metazoan-specific U8, are essential for rRNA processing, guiding cleavage in the 50-ETS, ITS1, and 30-ETS (Watkins and Bohnsack, 2012). rRNAs and ribosomal proteins are further assembled into the two ribosomal subunits: 18S rRNA into the small 40S and 28S, 5.8S, and 5S rRNAs into the large 60S ribosomal subunit
Vertebrate Rexo5 orthologs display a unique domain architecture of an RNase T domain paired with two RNA-recognition motifs (RRMs), which are absent in invertebrates (Figure 2B) (Finn et al, 2010)

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Ribosome biogenesis is central to protein synthesis and perhaps the most complex RNA metabolic process in eukaryotic cells, involving more than 200 ribosomal proteins and assembly factors in Saccharomyces cerevisiae and over 400 in human cells (Lafontaine, 2015; Tafforeau et al, 2013). Precursor rRNA (pre-rRNA) processing is conserved among eukaryotes, but with increasing organismal complexity, additional proteins and processing pathways evolved in speciation (Henras et al, 2015). The 8- to 13-kb-long 47S rRNA precursor transcript (37S in S. cerevisiae) contains 18S, 5.8S, and 28S rRNAs and is transcribed from multi-copy rDNA loci by RNA polymerase (Pol) I (Miller and Beatty, 1969; Mullineux and Lafontaine, 2012). The precursor of 5S rRNA is transcribed separately by RNA Pol III in the nucleus from a multi-copy 5S rDNA array (Ciganda and Williams, 2011). C/D and H/ACA small nucleolar RNA (snoRNA) ribonucleoprotein complexes introduce site-specific 20-O-methylation and pseudouridylation into rRNAs, which determine rRNA folding, translational activity, and innate nucleic acid sensing (Roers et al, 2016; Sharma and Lafontaine, 2015). A subset of snoRNAs, including U3 and the metazoan-specific U8, are essential for rRNA processing, guiding cleavage in the 50-ETS, ITS1, and 30-ETS (Watkins and Bohnsack, 2012). rRNAs and ribosomal proteins are further assembled into the two ribosomal subunits: 18S rRNA into the small 40S and 28S, 5.8S, and 5S rRNAs into the large 60S ribosomal subunit

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