The emerging landscape of small nucleolar RNAs in cell biology.
Bottom Line: As a family, they have been well characterized as playing a central role in ribosome biogenesis, guiding either the sequence-specific chemical modification of pre-rRNA (ribosomal RNA) or its processing.In recent years, thanks in great part to advances in sequencing methodologies, we have seen many examples of the diversity that exists in the snoRNA family on multiple levels.Under the deluge of novel features and functions that have recently come to light, snoRNAs emerge as a central, dynamic, and highly versatile group of small regulatory RNAs.
Affiliation: Biochemistry Department, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada.Show MeSH
Mentions: In addition to the SNORD115 family proposed to regulate the alternative splicing of a handful of pre-mRNA including the serotonin 2C receptor,40,55 and the SNORD116 family proposed to regulate the availability of the splicing factor RBFOX2,41 it has been suggested that other snoRNAs participate in pre-mRNA maturation (Table 3). SNORD88C (HBII-180C), a box C/D snoRNA with a box D′ guide sequence complementary to 28S rRNA, was also shown to harbor a region of complementarity to intronic portions of several pre-mRNA including the fibroblast growth factor receptor 3 (FGFR3), immediately downstream from its box D′, termed the M-box56 (Figure 3). The overexpression of a mini-gene containing part of the FGFR3 pre-mRNA including the target region resulted in the appearance of a splicing isoform of endogenous FGFR3 that was recapitulated in a cell line that naturally expresses SNORD88C at a low level.56 The long region of complementarity to several different pre-mRNAs and its unusual position (immediately downstream from the box D′ rather than upstream, as shown in Figure 3) prompted further investigation, and it was found that artificial SNORD88C constructs with a modified M-box could mediate the knockdown of complementary targets.78 Such snoMEN were thus proposed as a novel technology for the modulation of gene expression, which can easily be used for the generation of stable cell lines with targeted protein replacement.78,79 Supporting these findings, other artificial snoRNAs were also shown to regulate the splicing and maturation of specific targets. Analogs of the box C/D snoRNA U24 were designed with altered box D guide sequences, introducing complementarity to key positions in the second intron of the chaperone HSPA8.80 Antisense elements to the branch point, splice donor and acceptor sites, as well as the first and last nucleotides of the intron all resulted in increased alternative splicing and increased production of a known minor isoform of HSPA8.80 In a follow-up study, a subset of these artificial U24 snoRNAs directed at HSPA8 pre-mRNA were also shown to cause a significant decrease in mRNA levels.81 As for the snoMEN constructs,78 this knockdown effect was dependent on the complementary interaction between snoRNA and target, but independent of the ability of the snoRNA to guide methylation of the target.81
Affiliation: Biochemistry Department, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada.