Small nucleolar RNA
In
snoRNA guided modifications
After
- Methylation is the attachment or substitution of a 2′O-ribose-methylations (where the methyl group is attached to the ribose group).[1]
- Pseudouridylation is the conversion (isomerisation) of the nucleoside uridine to a different isomeric form pseudouridine (Ψ). This modification consists of a 180º rotation of the uridine base around its glycosyl bond to the ribose of the RNA backbone. After this rotation, the nitrogenous base contributes a carbon atom to the glycosyl bond instead of the usual nitrogen atom. The beneficial aspect of this modification is the additional hydrogen-bond donor available on the base. While uridine makes two hydrogen-bonds with its Watson-Crick base pair, adenine, pseudouridine is capable of making three hydrogen bonds. When pseudouridine is base-paired with adenine, it can also make another hydrogen bond, allowing the complexity of the mature rRNA structure to take form. The free hydrogen-bond donor often forms a bond with a base that is distant from itself, creating the tertiary structure that rRNA must have to be functional. Mature human rRNAs contain approximately 95 Ψ modifications.[1]
snoRNP
Each snoRNA molecule acts as a guide for only one (or two) individual modifications in a target RNA.
snoRNA guide families
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.[5] 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.[6]
C/D box
C/D box snoRNAs contain two short conserved sequence motifs, C (RUGAUGA) and D (CUGA), located near the
There exists a eukaryotic C/D box snoRNA (
H/ACA box
H/ACA box snoRNAs have a common
The RNA component of human telomerase (hTERC) contains an H/ACA domain for pre-RNP formation and nucleolar localization of the telomerase RNP itself.[13] 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.[14] 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.[15]
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.[15] Not all snoRNAs that have been localised to Cajal bodies are composite C/D and H/ACA box snoRNAs.
Orphan snoRNAs
The targets for newly identified snoRNAs are predicted on the basis of sequence complementarity between putative target RNAs and the antisense elements or recognition loops in the snoRNA sequence. However, there are increasing numbers of 'orphan' guides without any known RNA targets, which suggests that there might be more proteins or transcripts involved in rRNA than previously and/or that some snoRNAs have different functions not concerning rRNA.[16][17] There is evidence that some of these orphan snoRNAs regulate alternatively spliced transcripts.[18] 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.[19][20] Another C/D box snoRNA,
More recently, SNORD90 has been suggested to be able to guide N6-methyladenosine (m6A) modifications onto target RNA transcripts.[22] More specifically, Lin et al. demonstrated that SNORD90 can reduce the expression of neuregulin 3 (NRG3).[22]
Target modifications
The precise effect of the methylation and pseudouridylation modifications on the function of the mature RNAs is not yet known. The modifications do not appear to be essential but are known to subtly enhance the RNA folding and interaction with ribosomal proteins. In support of their importance, target site modifications are exclusively located within conserved and functionally important domains of the mature RNA and are commonly conserved among distant eukaryotes.[5] A novel method, Nm-REP-seq, was developed for enriching 2'-O-Methylations guided by C/D snoRNAs by using RNA exoribonuclease (Mycoplasma genitalium RNase R, MgR) and periodate oxidation reactivity to eliminate 2'-hydroxylated (2'-OH) nucleosides.[23]
- 2′-O-methylated ribose causes an increase in the 3′-endo conformation
- Pseudouridine (psi/Ψ) adds another option for H-bonding.
- Heavily methylated RNA is protected from hydrolysis. rRNA acts as a ribozyme by catalyzing its own hydrolysis and splicing.
Genomic organisation
SnoRNAs are located diversely in the genome. The majority of vertebrate snoRNA genes are encoded in the introns of genes encoding proteins involved in ribosome synthesis or translation, and are synthesized by RNA polymerase II. SnoRNAs are also shown to be located in intergenic regions, ORFs of protein coding genes, and UTRs.[24] SnoRNAs can also be transcribed from their own promoters by RNA polymerase II or III.
Imprinted loci
In the human genome, there are at least two examples where C/D box snoRNAs are found in tandem repeats within imprinted loci. These two loci (14q32 on chromosome 14 and 15q11q13 on chromosome 15) have been extensively characterised, and in both regions multiple snoRNAs have been found located within introns in clusters of closely related copies.
In 15q11q13, five different snoRNAs have been identified (
Region 14q32 contains repeats of two snoRNAs
Other functions
snoRNAs can function as
Recently, it has been found that snoRNAs can have functions not related to rRNA. One such function is the regulation of alternative splicing of the trans gene transcript, which is done by the snoRNA HBII-52, which is also known as SNORD115.[19]
In November 2012, Schubert et al. revealed that specific RNAs control chromatin compaction and accessibility in Drosophila cells.[37]
In July 2023, Lin et al. showed that snoRNAs have the potential to guide other RNA modifications, specifically N6-methyladenosine, however this is subject to further investigation.[22]
References
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