Non-coding RNA

A non-coding RNA (ncRNA) is any RNA molecule that is not translated into a protein. A previously used synonym, particularly with bacteria, was small RNA (sRNA). However, some ncRNAs are very large (e.g. Xist). Less-frequently used synonyms are non-messenger RNA (nmRNA), small non-messenger RNA (snmRNA), or functional RNA (fRNA). The DNA sequence from which a non-coding RNA is transcribed as the end product is often called an RNA gene or non-coding RNA gene (see gene).

Non-coding RNA genes include transfer RNA (tRNA) and ribosomal RNA (rRNA), small RNAs such as snoRNAs, microRNAs, siRNAs and piRNAs and lastly long ncRNAs that include examples such as Xist, Evf, Air, CTN and PINK. The number of ncRNAs encoded within the genome is unknown, however recent transcriptomic and microarray studies suggest the existence of over 30,000 long ncRNAs and at least as many small regulatory RNAs within the mouse genome alone. Since most of the newly identified ncRNAs have not been validated for their function, it is possible that majority of them is meaningless (e.g. non-functional or truncated transcript).

One of the major findings of the 2007 ENCODE Pilot Project was that "nearly the entire genome may be represented in primary transcripts that extensively overlap and include many non-protein-coding regions."^[1]

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Types of non-coding RNAs

tRNA

Main article: Transfer RNA

Transfer RNA (tRNA) is RNA that transfers the correct amino acid to a growing polypeptide chain at the ribosomal site of protein biosynthesis during translation.

rRNA

Main article: Ribosomal RNA

Ribosomal RNA (rRNA) is the primary constituent of ribosomes. Ribosomes are the protein-manufacturing organelles of cells and exist in the cytoplasm. rRNA is transcribed from DNA, like all RNA. Ribosomal proteins are transported into the nucleus and assembled together with rRNA before being transported through the nuclear membrane. This type of RNA makes up the vast majority of RNA found in a typical cell. While proteins are also present in the ribosomes, solely rRNA is able to form peptides. Therefore ribosomes, having a catalytic function, are a form of ribozyme.

Mammalian cells have 2 mitochondrial (23S and 16S) rRNA molecules [1] and 4 types of cytoplasmic rRNA (28S, 5.8S, 5S (large ribosome subunit) and 18S (small subunit)). 28S, 5.8S, and 18S rRNAs are encoded by a single transcription unit organized into 5 clusters (each has 30-40 repeats) on the 13,14,15,21,and 22 chromosomes. These are transcribed by RNA polymerase I. 5S occurs in tandem arrays (~200-300 true 5S genes and many dispersed pseudogenes), the largest one on the chromosome 1q41-42. 5S rRNA is transcribed by RNA polymerase III.

Cytoplasmic rRNA genes are highly repetitive because of huge demand of ribosomes for protein synthesis ('gene dosage') in the cell.

snRNA

Main articles: Small nuclear RNA and Small nucleolar RNA

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the nucleus of eukaryotic cells.

Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that guide chemical modifications (methylation or pseudouridylation) of ribosomal RNAs (rRNAs) and other RNA genes.

Small Cajal Body specific RNAs (scaRNAs) are a class of small RNA molecules similar to snoRNAs which specifically localize in the Cajal body, a nuclear organelle involved in the biogenesis of snRNPs. U85 is the first scaRNA ever described^[2]. Unlike typical snoRNAs, U85 scaRNA can guide both pseudouridylation and 2'-O-methylation.

miRNA

Main article: microRNA

microRNA (also miRNA) are RNA genes that are the reverse complement of portions of another gene's mRNA transcript and alter the expression of one or several genes through RNA interference. They are around 21-23 base pairs long in the mature form, and single-stranded. This sets them apart from small interfering RNAs (siRNA) which are about the same length, but double-stranded and derived from double-stranded RNA such as dsRNA viruses and small hairpin RNAs (shRNA).

gRNA

Main article: Guide RNA

gRNAs (for guide RNA) are RNA genes that function in RNA editing. Thus far, gRNA mediated RNA editing has been found only in the mitochondria of kinetoplastids, in which mRNAs are edited by inserting or deleting stretches of uridylates (Us). The gRNA forms part of the editosome and contains sequences that hybridize to matching sequences in the mRNA, to guide the mRNA modifications. Other types of RNA editing are found in many eukaryotes, including humans.

The term "guide RNA" is also sometimes used generically to mean any RNA gene that guides an RNA/protein complex via hybridization of matching sequences (e.g. snoRNAs).

piRNA

Main article: Piwi-interacting RNA

Piwi-interacting RNAs (piRNA) are active in ovaries and testes in animals, and cause gene silencing by interacting with Piwi proteins. They are similar to miRNAs, but somewhat longer and do not use dicer.^[3]

tmRNA

Main article: tmRNA

tmRNA has a complex structure with tRNA-like and mRNA-like regions. It has currently only been found in bacteria, but is ubiquitous in all bacteria. tmRNA recognizes ribosomes that have trouble translating or reading an mRNA and stall, leaving an unfinished protein that may be detrimental to the cell. tmRNA acts like a tRNA first, and then an mRNA that encodes a peptide tag. The ribosome translates this mRNA region of tmRNA and attaches the encoded peptide tag to the C-terminus of the unfinished protein. This attached tag targets the protein for destruction or proteolysis. How tmRNA works

Signal recognition particle RNA

The signal recognition particle (SRP) is an RNA-protein complex present in the cytoplasm of cells that binds to the mRNA of proteins that are destined for secretion from the cell. The RNA component of the SRP in eukaryotes is called 4.5S RNA.

Distinction between functional RNA (fRNA) and ncRNA

The term ncRNA has been used, in addition to its above definition, to describe regions of mRNA that are functional at the RNA level, i.e. they have a biological function other than coding for protein even though they are on a protein-coding mRNA, for example riboswitches and the SECIS element. They may even overlap with protein-coding sequence and are thus dual-function: at the RNA level and at the protein level (e.g. SgrS RNA and RNAIII). For example, the Rfam database main page uses the term "non-coding RNA families" to describe its content, although the database contains riboswitches, etc.

However, this may conflict with the Sequence Ontology's definition of ncRNA, which seems to require that a RNA does not contain any protein-coding sequence in order to be labeled ncRNA.

Several publications ^{[4] [5] [6]} have started using the term functional RNA (fRNA), as opposed to ncRNA, to describe regions functional at the RNA level that may or may not be stand-alone RNA transcripts. Therefore, every ncRNA is a fRNA, but there exist fRNA (such as riboswitches, SECIS elements, and other cis-regulatory regions) that are not ncRNA.

A significant reason for using the term fRNA is that many computational genome screens searching for ncRNA will also pick up riboswitches, etc. since they are looking for evidence of a RNA secondary structure that is conserved by evolution. Since a distinct structure is often required for function at the RNA level, any structurally-significant RNA (not just stand-alone RNA transcripts) will be discovered by the screen. Therefore, it is useful to have an umbrella term that describes both stand-alone transcripts that are completely non-coding (ncRNA) and functional RNA that is part of protein-coding mRNA.

Some publications ^[7] admit that the terms ncRNA and fRNA are nearly synonymous.

Untranslated regions of mRNAs

Main articles: Five prime untranslated region and Three prime untranslated region

Messenger RNA (mRNA) contains non-coding regions at its ends (called UTRs) which include riboswitches and the SECIS element. Although UTRs do not code for protein, mRNA is not considered to be non-coding RNA. Many of the functional elements in UTRs are cis-regulatory elements.

References

1. ^ George M. Weinstock (2007). "ENCODE: More genomic empowerment". Genome Research 17: 667-668.
2. ^ Jády BE, Kiss T (2001). "A small nucleolar guide RNA functions both in 2'-O-ribose methylation and pseudouridylation of the U5 spliceosomal RNA". EMBO J. 20 (3): 541-51. doi:10.1093/emboj/20.3.541. PMID 11157760.
3. ^ Alexei A. Aravin, Gregory J. Hannon, Julius Brennecke (2007). "The Piwi-piRNA Pathway Provides an Adaptive Defense in the Transposon Arms Race". Science 318 (5851): 761-764.
4. ^ Richard J. Carter, Inna Dubchak, Stephen R. Holbrook (2001). "A computational approach to identify genes for functional RNAs in genomic sequences". Nucleic Acids Research 29 (19): 3928–3938.
5. ^ Jakob Skou Pedersen, Gill Bejerano, Adam Siepel, Kate Rosenbloom, Kerstin Lindblad-Toh, Eric S. Lander, Jim Kent, Webb Miller, David Haussler (2006). "Identification and Classification of Conserved RNA Secondary Structures in the Human Genome". PLOS Computational Biology 2 (4): e33.
6. ^ Tomas Babak, Benjamin J Blencowe, Timothy R Hughes (2007). "Considerations in the identification of functional RNA structural elements in genomic alignments". BMC Bioinformatics (8): 33.
7. ^ Sean Eddy (2001). "Non–coding RNA genes and the modern RNA world". Nature Reviews Genetics (2): 919-929.