The emerging landscape of small nucleolar RNAs in cell biology

Abstract

Small nucleolar RNAs (snoRNAs) are a large class of small noncoding RNAs present in all eukaryotes sequenced thus far. 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. However, in higher eukaryotes, numerous orphan snoRNAs were described over a decade ago, with no known target or ascribed function, suggesting the possibility of alternative cellular functionality. 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. In this review, we discuss the identification of novel snoRNA members, of unexpected binding partners, as well as the clarification and extension of the snoRNA target space and the characterization of diverse new noncanonical functions, painting a new and extended picture of the snoRNA landscape. 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.

FIGURE 1

Features of small nucleolar RNAs (snoRNAs). (a) Box C/D snoRNAs are characterized by the presence of boxes C/C′ and D/D′ sequence motifs, represented in orange and cyan, respectively. Boxes C and D can interact forming noncanonical G–A pairings resulting in a structural motif called a k-turn (highlighted in purple). The k-turn is stabilized by the presence of canonical base pairing in proximity. Guide regions of box C/D snoRNAs, specifying the residue that will be methylated in the target, are found immediately upstream from the boxes D and/or D′ (shown in pink). The modified residue in the target is base paired with the snoRNA residue located exactly five nucleotides upstream from the box D or D′ (indicated by an asterisk). (b) Box H/ACA snoRNAs consist of two hairpins separated by a box H sequence motif (shown in purple) and followed by a box ACA found three nucleotides from the 3′ end (shown in red). The guide regions (shown in pink) specifying the residue that will be pseudouridylated (ψ) in the target are found in bulges in the hairpins and the modified residue is located 14–15 residues upstream from the box H or ACA.

FIGURE 2

Extent and diversity of box C/D small nucleolar RNA (snoRNA)-like molecules. While box C/D snoRNAs typically range between 60 and 90 nucleotides in length (a), mini-snoRNAs, binding the same interaction partners as classical snoRNAs, but lacking boxes C′ and D′ have been detected by sequencing (b). At the other end of the spectrum, snoRNA-lncRNA (long noncoding RNA) consisting of two box C/D snoRNAs and the intronic sequence separating them have also been reported (c). Many studies have also detected stable snoRNA-derived RNAs (sdRNAs) likely generated by the action of endonucleases or exonucleases. Some sdRNAs are miRNA-like– while others are longer products (d). Boxes C/C′ and D/D′ are represented, respectively, by orange and cyan colored boxes.

FIGURE 3

Sequence features of HBII-180C (SNORD88C). HBII-180C is a box C/D small nucleolar RNA (snoRNA) displaying boxes C (highlighted in orange), D′ and D (highlighted in cyan), as well as a guide region complementary to 28S rRNA specifying its methylation on position C3680. HBII-180C also has a region called the M-box (highlighted in pink) complementary to regions in specific pre-mRNA including FGFR3. The sequence shown for HBII-180C is the most abundant form detected by deep sequencing in multiple human cell lines and the structure was predicted using RNAfold.