Three prime untranslated region

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The flow of information within a cell. DNA is first transcribed into RNA, which is subsequently translated into protein. (See Central dogma of molecular biology). Central Dogma of Molecular Biochemistry with Enzymes.jpg
The flow of information within a cell. DNA is first transcribed into RNA, which is subsequently translated into protein. (See Central dogma of molecular biology).
mRNA structure, approximately to scale for a human mRNA, where the median length of 3'UTR is 700 nucleotides MRNA structure.svg
mRNA structure, approximately to scale for a human mRNA, where the median length of 3′UTR is 700 nucleotides

In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally influence gene expression.

Contents

During gene expression, an mRNA molecule is transcribed from the DNA sequence and is later translated into a protein. 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. Regulatory regions within the 3′-untranslated region can influence polyadenylation, translation efficiency, localization, and stability of the mRNA. [1] [2] The 3′-UTR contains binding sites for both regulatory proteins and microRNAs (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 elements (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 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, transport it to or from the cell nucleus, 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, 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 mammalian genome has considerable variation. This region of the mRNA transcript can range from 60 nucleotides to about 4000. [3] 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. [4] 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. [4]

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 elements (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. [1] Another set of elements that is present in both the 5' and 3′-UTR are iron response elements (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. [3]

Stem-loop structure of an RNA molecule Stem-loop.svg
Stem-loop structure of an RNA molecule

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. [1] The primary signal used is the nuclear polyadenylation signal (PAS) with the sequence AAUAAA located toward the end of the 3′-UTR. [3] 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. [3] 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 structure called the selenocysteine insertion sequence (SECIS) causes for the insertion of selenocysteine instead. [4]

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.

The role of miRNA in gene regulation Role of miRNA in a normal cell.svg
The role of miRNA in gene regulation

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 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, and adaptation to external stimuli. It therefore acts on transcripts encoding cytokines, growth factors, tumor suppressors, proto-oncogenes, cyclins, enzymes, transcription factors, receptors, and membrane proteins. [1]

Poly(A) tail

Circularization of the mRNA transcript is mediated by proteins interacting with the 5' cap and poly(A) tail. MRNAcircle.svg
Circularization of the mRNA transcript is mediated by proteins interacting with the 5' cap and 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. [1] [2] 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. [2]

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. [1] [2] [5] Human 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. [1]

Alternative polyadenylation results in transcripts with different 3'-UTRs Alternative polyadenylation.svg
Alternative polyadenylation results in transcripts with different 3′-UTRs

Alternative polyadenylation

Another mechanism involving the structure of the 3′-UTR is called alternative polyadenylation (APA), which results in mRNA isoforms that differ only in their 3′-UTRs. This mechanism is especially useful for complex organisms 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. [1] [5] [6]

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. [7] 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 and cross-linking techniques have enabled fine mapping of protein binding sites within the transcript. [8] 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. [9] These types of transcript-wide methods should help our understanding of known cis elements and trans-regulatory factors within 3′-UTRs.

Disease

Diseases caused by different mutations within the 3'-UTR UTR enfermedades 2 - multilingual.svg
Diseases caused by different mutations within the 3′-UTR

3′-UTR mutations can be very consequential because one alteration can be responsible for the altered expression of many genes. Transcriptionally, a mutation 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. [9] Dysregulation of ARE-binding proteins (AUBPs) due to mutations in AU-rich regions can lead to diseases including tumorigenesis (cancer), hematopoietic malignancies, leukemogenesis, and developmental delay/autism spectrum disorders. [10] [11] [12] An expanded number of trinucleotide (CTG) repeats in the 3’-UTR of the dystrophia myotonica protein kinase (DMPK) gene causes myotonic dystrophy. [7] Retro-transposal 3-kilobase insertion of tandem repeat sequences within the 3′-UTR of fukutin protein is linked to Fukuyama-type congenital muscular dystrophy. [7] Elements in the 3′-UTR have also been linked to human acute myeloid leukemia, alpha-thalassemia, neuroblastoma, Keratinopathy, Aniridia, IPEX syndrome, and congenital heart defects. [9] The few UTR-mediated diseases identified only hint at the countless links yet to be discovered.

Future development

Despite 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. [7] 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. [1]

See also

Related Research Articles

<span class="mw-page-title-main">Messenger RNA</span> RNA that is read by the ribosome to produce a protein

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.

<span class="mw-page-title-main">Gene expression</span> Conversion of a genes sequence into a mature gene product or products

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, proteins or non-coding RNA, and ultimately affect a phenotype. These products are often proteins, but in non-protein-coding genes such as transfer RNA (tRNA) and small nuclear RNA (snRNA), the product is a functional non-coding RNA. The process of gene expression is used by all known life—eukaryotes, prokaryotes, and utilized by viruses—to generate the macromolecular machinery for life.

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 eukaryotes, polyadenylation is part of the process that produces mature mRNA for translation. In many bacteria, the poly(A) tail promotes degradation of the mRNA. It, therefore, forms part of the larger process of gene expression.

The 5′ untranslated region is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA. In many organisms, however, the 5′ UTR is completely untranslated, instead forming a complex secondary structure to regulate translation.

<span class="mw-page-title-main">Post-transcriptional modification</span> RNA processing within a biological cell

Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, functional RNA molecule that can then leave the nucleus and perform any of a variety of different functions in the cell. There are many types of post-transcriptional modifications achieved through a diverse class of molecular mechanisms.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

Gene structure is the organisation of specialised sequence elements within a gene. Genes contain most of the information necessary for living cells to survive and reproduce. In most organisms, genes are made of DNA, where the particular DNA sequence determines the function of the gene. A gene is transcribed (copied) from DNA into RNA, which can either be non-coding (ncRNA) with a direct function, or an intermediate messenger (mRNA) that is then translated into protein. Each of these steps is controlled by specific sequence elements, or regions, within the gene. Every gene, therefore, requires multiple sequence elements to be functional. This includes the sequence that actually encodes the functional protein or ncRNA, as well as multiple regulatory sequence regions. These regions may be as short as a few base pairs, up to many thousands of base pairs long.

<span class="mw-page-title-main">Directionality (molecular biology)</span> End-to-end chemical orientation of a single strand of nucleic acid

Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-ring means that there will be a 5′ end, which frequently contains a phosphate group attached to the 5′ carbon of the ribose ring, and a 3′ end, which typically is unmodified from the ribose -OH substituent. In a DNA double helix, the strands run in opposite directions to permit base pairing between them, which is essential for replication or transcription of the encoded information.

Cleavage and polyadenylation specificity factor (CPSF) is involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription. In eukaryotes, messenger RNA precursors (pre-mRNA) are transcribed in the nucleus from DNA by the enzyme, RNA polymerase II. The pre-mRNA must undergo post-transcriptional modifications, forming mature RNA (mRNA), before they can be transported into the cytoplasm for translation into proteins. The post-transcriptional modifications are: the addition of a 5' m7G cap, splicing of intronic sequences, and 3' cleavage and polyadenylation.

<span class="mw-page-title-main">Long terminal repeat</span> DNA sequence

A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or a retroviral provirus. All retroviral genomes are flanked by LTRs, while there are some retrotransposons without LTRs. Typically, an element flanked by a pair of LTRs will encode a reverse transcriptase and an integrase, allowing the element to be copied and inserted at a different location of the genome. Copies of such an LTR-flanked element can often be found hundreds or thousands of times in a genome. LTR retrotransposons comprise about 8% of the human genome.

<span class="mw-page-title-main">Poly(A)-binding protein</span> RNA binding protein

Poly(A)-binding protein is an RNA-binding protein which triggers the binding of eukaryotic initiation factor 4 complex (eIF4G) directly to the poly(A) tail of mRNA which is 200-250 nucleotides long. The poly(A) tail is located on the 3' end of mRNA and was discovered by Mary Edmonds, who also characterized the poly-A polymerase enzyme that generates the poly(a) tail. The binding protein is also involved in mRNA precursors by helping polyadenylate polymerase add the poly(A) nucleotide tail to the pre-mRNA before translation. The nuclear isoform selectively binds to around 50 nucleotides and stimulates the activity of polyadenylate polymerase by increasing its affinity towards RNA. Poly(A)-binding protein is also present during stages of mRNA metabolism including nonsense-mediated decay and nucleocytoplasmic trafficking. The poly(A)-binding protein may also protect the tail from degradation and regulate mRNA production. Without these two proteins in-tandem, then the poly(A) tail would not be added and the RNA would degrade quickly.

<span class="mw-page-title-main">CPEB</span> Protein

CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA. CPEB is present at postsynaptic sites and dendrites where it stimulates polyadenylation and translation in response to synaptic activity. CPEB most commonly activates the target RNA for translation, but can also act as a repressor, dependent on its phosphorylation state. As a repressor, CPEB interacts with the deadenylation complex and shortens the polyadenine tail of mRNAs. In animals, CPEB is expressed in several alternative splicing isoforms that are specific to particular tissues and functions, including the self-cleaving Mammalian CPEB3 ribozyme. CPEB was first identified in Xenopus oocytes and associated with meiosis; a role has also been identified in the spermatogenesis of Caenorhabditis elegans.

The cytoplasmic polyadenylation element (CPE) is a sequence element found in the 3' untranslated region of messenger RNA. While several sequence elements are known to regulate cytoplasmic polyadenylation, CPE is the best characterized. The most common CPE sequence is UUUUAU, though there are other variations. Binding of CPE binding protein to this region promotes the extension of the existing polyadenine tail and, in general, activation of the mRNA for protein translation. This elongation occurs after the mRNA has been exported from the nucleus to the cytoplasm. A longer poly(A) tail attracts more cytoplasmic polyadenine binding proteins (PABPs) which interact with several other cytoplasmic proteins that encourage the mRNA and the ribosome to associate. The lengthening of the poly(A) tail thus has a role in increasing translational efficiency of the mRNA. The polyadenine tails are extended from approximately 40 bases to 150 bases.

<span class="mw-page-title-main">Untranslated region</span> Non-coding regions on either end of mRNA

In molecular genetics, an untranslated region refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR, or if it is found on the 3' side, it is called the 3' UTR. mRNA is RNA that carries information from DNA to the ribosome, the site of protein synthesis (translation) within a cell. The mRNA is initially transcribed from the corresponding DNA sequence and then translated into protein. However, several regions of the mRNA are usually not translated into protein, including the 5' and 3' UTRs.

<span class="mw-page-title-main">Gurken localisation signal</span>

mRNA localization is a common mode of posttranscriptional regulation of gene expression that targets a protein to its site of function. Proteins are highly dependent on cellular environments for stability and function, therefore, mRNA localization signals are crucial for maintaining protein function. The Gurken localisation signal is an RNA regulatory element conserved across many species of Drosophila. The element consists of an RNA stem loop within the coding region of the messenger RNA that forms a signal for dynein-mediated Gurken mRNA transport to the dorsoanterior cap near the nucleus of the oocyte.

<span class="mw-page-title-main">Rotavirus translation</span>

Rotavirus translation, the process of translating mRNA into proteins, occurs in a different way in Rotaviruses. Unlike the vast majority of cellular proteins in other organisms, in Rotaviruses the proteins are translated from capped but nonpolyadenylated mRNAs. The viral nonstructural protein NSP3 specifically binds the 3'-end consensus sequence of viral mRNAs and interacts with the eukaryotic translation initiation factor eIF4G. The Rotavirus replication cycle occurs entirely in the cytoplasm. Upon virus entry, the viral transcriptase synthesizes capped but nonpolyadenylated mRNA The viral mRNAs bear 5' and 3' untranslated regions (UTR) of variable length and are flanked by two different sequences common to all genes.

<span class="mw-page-title-main">CUGBP1</span> Protein-coding gene in the species Homo sapiens

CUG triplet repeat, RNA binding protein 1, also known as CUGBP1, is a protein which in humans is encoded by the CUGBP1 gene.

Adenylate-uridylate-rich elements 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 determinants of RNA stability in mammalian cells.

Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occurs between the transcription phase and the translation phase of gene expression. These controls are critical for the regulation of many genes across human tissues. It also plays a big role in cell physiology, being implicated in pathologies such as cancer and neurodegenerative diseases.

<span class="mw-page-title-main">Red clover necrotic mosaic virus translation enhancer elements</span>

Red clover necrotic mosaic virus (RCNMV) contains several structural elements present within the 3′ and 5′ untranslated regions (UTR) of the genome that enhance translation. In eukaryotes transcription is a prerequisite for translation. During transcription the pre-mRNA transcript is processes where a 5′ cap is attached onto mRNA and this 5′ cap allows for ribosome assembly onto the mRNA as it acts as a binding site for the eukaryotic initiation factor eIF4F. Once eIF4F is bound to the mRNA this protein complex interacts with the poly(A) binding protein which is present within the 3′ UTR and results in mRNA circularization. This multiprotein-mRNA complex then recruits the ribosome subunits and scans the mRNA until it reaches the start codon. Transcription of viral genomes differs from eukaryotes as viral genomes produce mRNA transcripts that lack a 5’ cap site. Despite lacking a cap site viral genes contain a structural element within the 5’ UTR known as an internal ribosome entry site (IRES). IRES is a structural element that recruits the 40s ribosome subunit to the mRNA within close proximity of the start codon.

References

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Further reading