The two different types of rRNA modification (methylation and pseudouridylation) are directed by two different families of snoRNAs. These families of snoRNAs are referred to as antisense C/D box and H/ACA box snoRNAs based on the presence of conserved sequence motifs in the snoRNA. There are exceptions, but as a general rule C/D box members guide methylation and H/ACA members guide pseudouridylation. The members of each family may vary in biogenesis, structure, and function, but each family is classified by the following generalised characteristics. For more detail, see review. SnoRNAs are classified under small nuclear RNA in
MeSH. The
HGNC, in collaboration with snoRNABase and experts in the field, has approved unique names for human genes that encode snoRNAs.
C/D box database. This example is
SNORD73 (RF00071). C/D box snoRNAs contain two short conserved sequence motifs, C (RUGAUGA) and D (CUGA), located near the
5′ and
3′ ends of the snoRNA, respectively. Short regions (~ 5 nucleotides) located
upstream of the C box and
downstream of the D box are usually base complementary and form a stem-box structure, which brings the C and D box motifs into close proximity. This stem-box structure has been shown to be essential for correct snoRNA synthesis and nucleolar localization. Many C/D box snoRNA also contain an additional less-well-conserved copy of the C and D motifs (referred to as C' and D') located in the central portion of the snoRNA molecule. A conserved region of 10–21 nucleotides upstream of the D box is complementary to the methylation site of the target RNA and enables the snoRNA to form an RNA duplex with the RNA. The nucleotide to be modified in the target RNA is usually located at the 5th position upstream from the D box (or D' box). C/D box snoRNAs associate with four evolutionary conserved and essential proteins—
fibrillarin (Nop1p),
NOP56,
NOP58, and
SNU13 (15.5-kD protein in eukaryotes; its archaeal homolog is L7Ae)—which make up the core C/D box snoRNP. The hairpin regions contain internal bulges known as recognition loops in which the antisense guide sequences (bases complementary to the target sequence) are located. These guide sequences essentially mark the location of the uridine on the target rRNA that is going to be modified. This recognition sequence is bipartite (constructed from the two different arms of the loop region) and forms complex
pseudo-knots with the target RNA. H/ACA box snoRNAs associate with four evolutionary conserved and essential proteins—
dyskerin (Cbf5p),
GAR1,
NHP2, and
NOP10—which make up the core of the H/ACA box snoRNP. Like Trypanosomes,
Entamoeba histolytica has mix population of single hairpin as well as double hairpin H/ACA box snoRNAs. It was reported that there occurred processing of the double hairpin H/ACA box snoRNA to the single hairpin snoRNAs however, unlike trypanosomes, it has a regular ACA motif at 3′ tail.[19] The RNA component of human
telomerase (hTERC) contains an H/ACA domain for pre-RNP formation and nucleolar localization of the telomerase RNP itself. The H/ACA snoRNP has been implicated in the rare genetic disease
dyskeratosis congenita (DKC) due to its affiliation with human telomerase. Mutations in the protein component of the H/ACA snoRNP result in a reduction in physiological TERC levels. This has been strongly correlated with the pathology behind DKC, which seems to be primarily a disease of poor
telomere maintenance.
Composite H/ACA and C/D box An unusual guide snoRNA U85 that functions in both 2′-O-ribose methylation and pseudouridylation of
small nuclear RNA (snRNA) U5 has been identified. This composite snoRNA contains both C/D and H/ACA box domains and associates with the proteins specific to each class of snoRNA (fibrillarin and Gar1p, respectively). More composite snoRNAs have now been characterised. These composite snoRNAs have been found to accumulate in a subnuclear organelle called the
Cajal body and are referred to as
small Cajal body-specific RNAs (scaRNAs). This is in contrast to the majority of C/D box or H/ACA box snoRNAs, which localise to the nucleolus. These Cajal body specific RNAs are proposed to be involved in the modification of RNA polymerase II transcribed spliceosomal RNAs U1, U2, U4, U5 and U12. There is evidence that some of these orphan snoRNAs regulate alternatively spliced transcripts. For example, it appears that the C/D box snoRNA
SNORD115 regulates the alternative splicing of the
serotonin 2C receptor mRNA via a conserved region of complementarity. Another C/D box snoRNA,
SNORD116, that resides in the same cluster as SNORD115 has been predicted to have 23 possible targets within protein coding genes using a
bioinformatic approach. Of these, a large fraction were found to be alternatively spliced, suggesting a role of SNORD116 in the regulation of alternative splicing. More recently,
SNORD90 has been suggested to be able to guide
N6-methyladenosine (m6A) modifications onto target RNA transcripts. More specifically, Lin et al. demonstrated that SNORD90 can reduce the expression of
neuregulin 3 (NRG3). == Target modifications ==