Three Prime Untranslated Region
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molecular genetics Molecular genetics is a sub-field of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the ...
, the three prime untranslated region (3′-UTR) is the section of
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
(mRNA) that immediately follows the
translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
termination codon In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in mess ...
. The 3′-UTR often contains regulatory regions that post-transcriptionally influence
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
. During
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
, an mRNA molecule is transcribed from the DNA sequence and is later
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
into a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. Several regions of the mRNA molecule are not translated into a protein including the 5' cap, 5' untranslated region, 3′ untranslated region and
poly(A) tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...
. Regulatory regions within the 3′-untranslated region can influence
polyadenylation Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...
, translation efficiency, localization, and stability of the mRNA. The 3′-UTR contains both binding sites for regulatory proteins as well as
microRNAs MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...
(miRNAs). By binding to specific sites within the 3′-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting translation or directly causing degradation of the transcript. The 3′-UTR also has silencer regions which bind to repressor proteins and will inhibit the expression of the mRNA. Many 3′-UTRs also contain
AU-rich element Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common de ...
s (AREs). Proteins bind AREs to affect the stability or decay rate of transcripts in a localized manner or affect translation initiation. Furthermore, the 3′-UTR contains the sequence AAUAAA that directs addition of several hundred adenine residues called the
poly(A) tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euk ...
to the end of the mRNA transcript. Poly(A) binding protein (PABP) binds to this tail, contributing to regulation of mRNA translation, stability, and export. For example, poly(A) tail bound PABP interacts with proteins associated with the 5' end of the transcript, causing a circularization of the mRNA that promotes translation. The 3′-UTR can also contain sequences that attract proteins to associate the mRNA with the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
, transport it to or from the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
, or perform other types of localization. In addition to sequences within the 3′-UTR, the physical characteristics of the region, including its length and
secondary structure Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
, contribute to translation regulation. These diverse mechanisms of gene regulation ensure that the correct genes are expressed in the correct cells at the appropriate times.


Physical characteristics

The 3′-UTR of mRNA has a great variety of regulatory functions that are controlled by the physical characteristics of the region. One such characteristic is the length of the 3′-UTR, which in the
mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian genome has considerable variation. This region of the mRNA transcript can range from 60
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s to about 4000. On average the length for the 3′-UTR in humans is approximately 800 nucleotides, while the average length of 5'-UTRs is only about 200 nucleotides. The length of the 3′-UTR is significant since longer 3′-UTRs are associated with lower levels of gene expression. One possible explanation for this phenomenon is that longer regions have a higher probability of possessing more miRNA binding sites that have the ability to inhibit translation. In addition to length, the nucleotide composition also differs significantly between the 5' and 3′-UTR. The mean G+C percentage of the 5'-UTR in warm-blooded vertebrates is about 60% as compared to only 45% for 3′-UTRs. This is important because an inverse correlation has been observed between the G+C% of 5' and 3′-UTRs and their corresponding lengths. The UTRs that are GC-poor tend to be longer than those located in GC-rich genomic regions. Sequences within the 3′-UTR also have the ability to degrade or stabilize the mRNA transcript. Modifications that control a transcript's stability allow expression of a gene to be rapidly controlled without altering translation rates. One group of elements in the 3′-UTR that can help destabilize an mRNA transcript are the
AU-rich element Adenylate-uridylate-rich elements (AU-rich elements; AREs) are found in the 3' untranslated region (UTR) of many messenger RNAs (mRNAs) that code for proto-oncogenes, nuclear transcription factors, and cytokines. AREs are one of the most common de ...
s (AREs). These elements range in size from 50 to 150 base pairs and generally contain multiple copies of the pentanucleotide AUUUA. Early studies indicated that AREs can vary in sequence and fall into three main classes that differ in the number and arrangement of motifs. Another set of elements that is present in both the 5' and 3′-UTR are
iron response element In molecular biology, the iron response element or iron-responsive element (IRE) is a short conserved stem-loop which is bound by Iron-responsive element binding protein, iron response proteins (IRPs, also named IRE-BP or IRBP). The IRE is found ...
s (IREs). The IRE is a stem-loop structure within the untranslated regions of mRNAs that encode proteins involved in cellular iron metabolism. The mRNA transcript containing this element is either degraded or stabilized depending upon the binding of specific proteins and the intracellular iron concentrations. The 3′-UTR also contains sequences that signal additions to be made, either to the transcript itself or to the product of translation. For example, there are two different polyadenylation signals present within the 3′-UTR that signal the addition of the poly(A) tail. These signals initiate the synthesis of the poly(A) tail at a defined length of about 250 base pairs. The primary signal used is the nuclear polyadenylation signal (PAS) with the sequence AAUAAA located toward the end of the 3′-UTR. However, during early development cytoplasmic polyadenylation can occur instead and regulate the translational activation of maternal mRNAs. The element that controls this process is called the CPE which is AU-rich and located in the 3′-UTR as well. The CPE generally has the structure UUUUUUAU and is usually within 100 base pairs of the nuclear PAS. Another specific addition signaled by the 3′-UTR is the incorporation of selenocysteine at UGA codons of mRNAs encoding selenoproteins. Normally the UGA codon encodes for a stop of translation, but in this case a conserved
stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when ...
structure called the selenocysteine insertion sequence (SECIS) causes for the insertion of selenocysteine instead.


Role in gene expression

The 3′-untranslated region plays a crucial role in gene expression by influencing the localization, stability, export, and translation efficiency of an mRNA. It contains various sequences that are involved in gene expression, including microRNA response elements (MREs), AU-rich elements (AREs), and the poly(A) tail. In addition, the structural characteristics of the 3′-UTR as well as its use of alternative polyadenylation play a role in gene expression.


MicroRNA response elements

The 3′-UTR often contains microRNA response elements (MREs), which are sequences to which miRNAs bind. miRNAs are short, non-coding RNA molecules capable of binding to mRNA transcripts and regulating their expression. One miRNA mechanism involves partial
base pairing A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
of the 5' seed sequence of an miRNA to an MRE within the 3′-UTR of an mRNA; this binding then causes translational repression.


AU-rich elements

In addition to containing MREs, the 3′-UTR also often contains AU-rich elements (AREs), which are 50 to 150 bp in length and usually include many copies of the sequence AUUUA. ARE binding proteins (ARE-BPs) bind to AU-rich elements in a manner that is dependent upon tissue type, cell type, timing, cellular localization, and environment. In response to different intracellular and extracellular signals, ARE-BPs can promote mRNA decay, affect mRNA stability, or activate translation. This mechanism of gene regulation is involved in cell growth,
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
, and adaptation to external stimuli. It therefore acts on transcripts encoding
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
,
growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...
, tumor suppressors,
proto-oncogenes An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
,
cyclins Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle. Etymology Cyclins were originally di ...
,
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
,
transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
,
receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
, and
membrane proteins Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
.


Poly(A) tail

The poly(A) tail contains binding sites for poly(A) binding proteins (PABPs). These proteins cooperate with other factors to affect the export, stability, decay, and translation of an mRNA. PABPs bound to the poly(A) tail may also interact with proteins, such as translation initiation factors, that are bound to the 5' cap of the mRNA. This interaction causes circularization of the transcript, which subsequently promotes translation initiation. Furthermore, it allows for efficient translation by causing recycling of
ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
. While the presence of a poly(A) tail usually aids in triggering translation, the absence or removal of one often leads to exonuclease-mediated degradation of the mRNA. Polyadenylation itself is regulated by sequences within the 3′-UTR of the transcript. These sequences include cytoplasmic polyadenylation elements (CPEs), which are uridine-rich sequences that contribute to both polyadenylation activation and repression. CPE-binding protein (CPEB) binds to CPEs in conjunction with a variety of other proteins in order to elicit different responses.


Structural characteristics

While the sequence that constitutes the 3′-UTR contributes greatly to gene expression, the structural characteristics of the 3′-UTR also play a large role. In general, longer 3′-UTRs correspond to lower expression rates since they often contain more miRNA and protein binding sites that are involved in inhibiting translation.
Human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
transcripts possess 3′-UTRs that are on average twice as long as other mammalian 3′-UTRs. This trend reflects the high level of complexity involved in human gene regulation. In addition to length, the secondary structure of the 3′-untranslated region also has regulatory functions. Protein factors can either aid or disrupt folding of the region into various secondary structures. The most common structure is a stem-loop, which provides a scaffold for RNA binding proteins and non-coding RNAs that influence expression of the transcript.


Alternative polyadenylation

Another mechanism involving the structure of the 3′-UTR is called alternative polyadenylation (APA), which results in mRNA
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
s that differ only in their 3′-UTRs. This mechanism is especially useful for complex
organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...
s as it provides a means of expressing the same protein but in varying amounts and locations. It is utilized by about half of human genes. APA can result from the presence of multiple polyadenylation sites or mutually exclusive terminal exons. Since it can affect the presence of protein and miRNA binding sites, APA can cause differential expression of mRNA transcripts by influencing their stability, export to the cytoplasm, and translation efficiency.


Methods of study

Scientists use a number of methods to study the complex structures and functions of the 3′ UTR. Even if a given 3′-UTR in an mRNA is shown to be present in a tissue, the effects of localization, functional half-life, translational efficiency, and trans-acting elements must be determined to understand the 3′-UTR's full functionality. Computational approaches, primarily by sequence analysis, have shown the existence of AREs in approximately 5 to 8% of human 3′-UTRs and the presence of one or more miRNA targets in as many as 60% or more of human 3′-UTRs. Software can rapidly compare millions of sequences at once to find similarities between various 3′ UTRs within the genome. Experimental approaches have been used to define sequences that associate with specific RNA-binding proteins; specifically, recent improvements in
sequencing In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succ ...
and cross-linking techniques have enabled fine mapping of protein binding sites within the transcript. Induced site-specific mutations, for example those that affect the termination codon, polyadenylation signal, or secondary structure of the 3′-UTR, can show how mutated regions can cause translation deregulation and disease. These types of transcript-wide methods should help our understanding of known cis elements and trans-regulatory factors within 3′-UTRs.


Disease

3′-UTR mutations can be very consequential because one alteration can be responsible for the altered expression of many genes. Transcriptionally, a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
may affect only the allele and genes that are physically linked. However, since 3′-UTR binding proteins also function in the processing and nuclear export of mRNA, a mutation can also affect other unrelated genes. Dysregulation of ARE-binding proteins (AUBPs) due to mutations in AU-rich regions can lead to diseases including
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
(cancer), hematopoietic malignancies, leukemogenesis, and developmental delay/autism spectrum disorders. An expanded number of trinucleotide (CTG) repeats in the 3’-UTR of the dystrophia myotonica protein kinase (DMPK) gene causes
myotonic dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intel ...
. Retro-transposal 3-kilobase insertion of tandem repeat sequences within the 3′-UTR of fukutin protein is linked to Fukuyama-type congenital muscular dystrophy. Elements in the 3′-UTR have also been linked to human
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...
,
alpha-thalassemia Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the genes '' HBA1'' and '' HBA2''. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule ...
,
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...
, Keratinopathy, Aniridia,
IPEX syndrome Immunodysregulation polyendocrinopathy enteropathy X-linked (or IPEX) syndrome is a rare disease linked to the dysfunction of the gene encoding transcription factor forkhead box P3 (FOXP3), widely considered to be the master regulator of the regul ...
, and
congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
s. The few UTR-mediated diseases identified only hint at the countless links yet to be discovered.


Future development

Despite our current understanding of 3′-UTRs, they are still relative mysteries. Since mRNAs usually contain several overlapping control elements, it is often difficult to specify the identity and function of each 3′-UTR element, let alone the regulatory factors that may bind at these sites. Additionally, each 3′-UTR contains many alternative AU-rich elements and polyadenylation signals. These cis- and trans-acting elements, along with miRNAs, offer a virtually limitless range of control possibilities within a single mRNA. Future research through the increased use of deep-sequencing based ribosome profiling will reveal more regulatory subtleties as well as new control elements and AUBPs. Furthermore, the ultimate fate of a transcript lies in the
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathway that it is involved in, so future research in this area appears promising.


See also

*
Five prime untranslated region The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of t ...
*
UTRdb UTRdb is a database of 5' and 3' untranslated sequences of eukaryotic mRNAs See also * Five prime untranslated region * Three prime untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of ...
*
UTRome UTRome is a database of three-prime untranslated regions in C. elegans See also * untranslated region (UTR) * UTRdb UTRdb is a database of 5' and 3' untranslated sequences of eukaryotic mRNAs See also * Five prime untranslated region * Thre ...


References


Further reading

*


External links


Brief introduction to mRNA regulatory elementsUTResource
3′ UTR analysis
UTRome.org
3′ UTRs in nematodes * Medical Subject Heading
3′ Untranslated Regions
{{Use dmy dates, date=April 2017 RNA Gene expression