323:. 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.
31:
375:
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
389:
237:
341:
266:, 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,
43:
311:
196:
188:(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
192:(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.
450:
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
379:
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
374:
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
336:
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
174:
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
142:
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
179:
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
400:
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
331:
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
318:
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
232:
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
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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
215:
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
206:
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
449:
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.
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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
138:(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
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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
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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.
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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
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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
413:. 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
216:
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
123:(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
366:. 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.
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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
405:(cancer), hematopoietic malignancies, leukemogenesis, and developmental delay/autism spectrum disorders. An expanded number of trinucleotide (CTG) repeats in the 3’-UTR of the
158:, 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.
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deregulation and disease. These types of transcript-wide methods should help our understanding of known cis elements and trans-regulatory factors within 3′-UTRs.
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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.
841:
Conne, Béatrice; Stutz, André; Vassalli, Jean-Dominique (1 June 2000). "The 3′ untranslated region of messenger RNA: A molecular 'hotspot' for pathology?".
154:, or perform other types of localization. In addition to sequences within the 3′-UTR, the physical characteristics of the region, including its length and
1073:"A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR"
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3′-UTR mutations can be very consequential because one alteration can be responsible for the altered expression of many genes. Transcriptionally, a
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119:, translation efficiency, localization, and stability of the mRNA. The 3′-UTR contains binding sites for both regulatory proteins and
35:
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Pichon, Xavier; A. Wilson, Lindsay; Stoneley, Mark; Bastide, Amandine; A King, Helen; Somers, Joanna; E Willis, Anne (1 July 2012).
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of the 5' seed sequence of an miRNA to an MRE within the 3′-UTR of an mRNA; this binding then causes translational repression.
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The flow of information within a cell. DNA is first transcribed into RNA, which is subsequently translated into protein. (See
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Another mechanism involving the structure of the 3′-UTR is called alternative polyadenylation (APA), which results in mRNA
938:
Chatterjee, Sangeeta; Pal, Jayanta K. (1 May 2009). "Role of 5'- and 3′-untranslated regions of mRNAs in human diseases".
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signal (PAS) with the sequence AAUAAA located toward the end of the 3′-UTR. However, during early development
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Circularization of the mRNA transcript is mediated by proteins interacting with the 5' cap and poly(A) tail.
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mRNA structure, approximately to scale for a human mRNA, where the median length of 3′UTR is 700 nucleotides
1174:
1134:
Mazumder B, Seshadri V, Fox PL (2003). "Translational control by the 3′-UTR: the ends specify the means".
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synthesis of the poly(A) tail at a defined length of about 250 base pairs. The primary signal used is the
512:"Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements"
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1024:"Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements"
441:. The few UTR-mediated diseases identified only hint at the countless links yet to be discovered.
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genome has considerable variation. This region of the mRNA transcript can range from 60
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that differ only in their 3′-UTRs. This mechanism is especially useful for complex
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will reveal more regulatory subtleties as well as new control elements and AUBPs.
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Giammartino, Dafne Campigli; Nishida, Kensei; Manley, James L. (2011).
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Alternative polyadenylation results in transcripts with different 3′-UTRs
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Sequence at the 3' end of messenger RNA that does not code for product
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115:. Regulatory regions within the 3′-untranslated region can influence
886:"Toward a Systematic Understanding of mRNA 3′ Untranslated Regions"
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Barrett, Lucy W.; Fletcher, Sue; Wilton, Steve D. (27 April 2012).
983:"AU-rich RNA binding proteins in hematopoiesis and leukemogenesis"
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Zhao, W.; Blagev, D.; Pollack, J. L.; Erle, D. J. (4 May 2011).
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In addition to containing MREs, the 3′-UTR also often contains
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Hesketh, John (23 September 2005). "3′ UTRs and
Regulation".
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Baou, M.; Norton, J. D.; Murphy, J. J. (13 September 2011).
738:"Mechanisms and Consequences of Alternative Polyadenylation"
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Diseases caused by different mutations within the 3′-UTR
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proteins and will inhibit the expression of the mRNA.
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causes for the insertion of selenocysteine instead.
73:. The 3′-UTR often contains regulatory regions that
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Proceedings of the
National Academy of Sciences USA
680:Mignone, Flavio; Graziano Pesole (15 August 2011).
787:"Ending the message: poly(A) signals then and now"
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1170:Brief introduction to mRNA regulatory elements
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1071:Suhl, Joshua A. (24 November 2015).
1028:Cellular and Molecular Life Sciences
1022:Khabar, Khalid S. A. (22 May 2010).
516:Cellular and Molecular Life Sciences
240:The role of miRNA in gene regulation
66:(mRNA) that immediately follows the
690:10.1002/9780470015902.a0005009.pub2
407:dystrophia myotonica protein kinase
36:Central dogma of molecular biology
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682:mRNA Untranslated Regions (UTRs)
75:post-transcriptionally influence
56:three prime untranslated region
464:Five prime untranslated region
150:, transport it to or from the
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111:, 3′ untranslated region and
1000:10.1182/blood-2011-07-347237
754:10.1016/j.molcel.2011.08.017
202:structure of an RNA molecule
401:lead to diseases including
349:Alternative polyadenylation
332:in inhibiting translation.
213:cytoplasmic polyadenylation
143:that promotes translation.
18:3' untranslated region
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584:10.2174/138920312801619475
327:Structural characteristics
245:MicroRNA response elements
134:Many 3′-UTRs also contain
1040:10.1007/s00018-010-0383-x
902:10.1513/pats.201007-054MS
785:Proudfoot, N. J. (2011).
528:10.1007/s00018-012-0990-9
439:congenital heart defects
268:cellular differentiation
184:mRNA transcript are the
162:Physical characteristics
1191:3′ Untranslated Regions
1187:Medical Subject Heading
1098:10.1073/pnas.1514260112
791:Genes & Development
632:10.1038/npg.els.0005011
264:AU-rich elements (AREs)
228:Role in gene expression
209:nuclear polyadenylation
415:acute myeloid leukemia
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190:iron response elements
127:regions which bind to
109:5' untranslated region
95:sequence and is later
87:, an mRNA molecule is
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624:3′UTRs and Regulation
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292:transcription factors
278:, tumor suppressors,
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220:structure called the
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1183:3′ UTRs in nematodes
803:10.1101/gad.17268411
62:) is the section of
1136:Trends Biochem. Sci
1089:2015PNAS..112E6553S
940:Biology of the Cell
409:(DMPK) gene causes
156:secondary structure
952:10.1042/BC20080104
452:ribosome profiling
445:Future development
411:myotonic dystrophy
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52:molecular genetics
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419:alpha-thalassemia
300:membrane proteins
180:genomic regions.
71:termination codon
16:(Redirected from
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1142:(2): 91–8.
172:nucleotides
89:transcribed
68:translation
1202:Categories
1181:UTRome.org
1175:UTResource
480:References
377:sequencing
97:translated
718:ignored (
708:cite book
660:ignored (
650:cite book
359:organisms
321:ribosomes
296:receptors
272:cytokines
218:stem-loop
200:Stem-loop
168:mammalian
129:repressor
121:microRNAs
91:from the
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1058:20495997
1009:21917750
968:22689654
960:19275763
920:21543795
863:10835679
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602:22708490
546:22538991
458:See also
431:Aniridia
398:mutation
355:isoforms
125:silencer
1108:4664359
1085:Bibcode
1049:2921490
911:3131834
871:7718209
812:3175714
763:3194005
593:3431537
537:3474909
384:Disease
288:enzymes
284:cyclins
101:protein
99:into a
83:During
1154:
1115:
1105:
1056:
1046:
1007:
966:
958:
918:
908:
869:
861:
819:
809:
770:
760:
696:
638:
600:
590:
544:
534:
474:UTRome
437:, and
298:, and
105:5' cap
60:3′-UTR
54:, the
987:Blood
964:S2CID
867:S2CID
469:UTRdb
364:exons
334:Human
1152:PMID
1113:PMID
1054:PMID
1005:PMID
956:PMID
916:PMID
859:PMID
817:PMID
768:PMID
720:help
694:ISBN
662:help
636:ISBN
598:PMID
542:PMID
1208:RNA
1144:doi
1103:PMC
1093:doi
1081:112
1044:PMC
1036:doi
995:doi
991:118
948:doi
944:101
906:PMC
898:doi
851:doi
807:PMC
799:doi
758:PMC
750:doi
686:doi
628:doi
588:PMC
580:doi
532:PMC
524:doi
93:DNA
50:In
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