Limits...
Before It Gets Started: Regulating Translation at the 5' UTR.

Araujo PR, Yoon K, Ko D, Smith AD, Qiao M, Suresh U, Burns SC, Penalva LO - Comp. Funct. Genomics (2012)

Bottom Line: Translation regulation plays important roles in both normal physiological conditions and diseases states.This regulation requires cis-regulatory elements located mostly in 5' and 3' UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity.In this paper, we discuss important aspects of 5' UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

View Article: PubMed Central - PubMed

Affiliation: Greehey Children's Cancer Research Institute, UTHSCSA, San Antonio, TX 78229-3900, USA.

ABSTRACT
Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5' and 3' UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5' UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

No MeSH data available.


Related in: MedlinePlus

Translational regulation by RNA binding proteins. (a) In iron-deficient cells, IRPs bind to the IRE localized in the 5′ UTR of ferritin mRNA, blocking its translation. Once cellular iron levels increase, a complex containing Fe binds to IRPs. Thus, these proteins are allosterically modified, which reduces IRP-IRE binding and allows the translation of ferritin mRNAs. (b) msl-2 gene regulation in females flies. After transcription in the nucleus, SXL specifically binds to intronic U-rich regions of msl-2 pre-mRNA and inhibits the intron removal (1). In the cytoplasm, SXL binds to the same elements localized now in the 5′ UTR of mature msl-2 mRNA, enhances the translation initiation of a upstream ORF (2), and prevents the main ORF translation (3). The regulatory elements in the 3′ UTR of msl-2 mRNA were not represented.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3368165&req=5

fig2: Translational regulation by RNA binding proteins. (a) In iron-deficient cells, IRPs bind to the IRE localized in the 5′ UTR of ferritin mRNA, blocking its translation. Once cellular iron levels increase, a complex containing Fe binds to IRPs. Thus, these proteins are allosterically modified, which reduces IRP-IRE binding and allows the translation of ferritin mRNAs. (b) msl-2 gene regulation in females flies. After transcription in the nucleus, SXL specifically binds to intronic U-rich regions of msl-2 pre-mRNA and inhibits the intron removal (1). In the cytoplasm, SXL binds to the same elements localized now in the 5′ UTR of mature msl-2 mRNA, enhances the translation initiation of a upstream ORF (2), and prevents the main ORF translation (3). The regulatory elements in the 3′ UTR of msl-2 mRNA were not represented.

Mentions: The best characterized example of RBP-mediated regulation involving 5′ UTRs is provided by the iron regulatory proteins (IRP 1 and 2). These proteins recognize a highly conserved stem loop structure with circa 30 nucleotides, known as the iron response element (IRE). The most important features include a hexanucleotide loop with the sequence CAGYCX (Y = U or A; X = U, C, or A) and a 5 bp upper stem that is separated from a lower stem of variable length by an unpaired cytosine. This regulation is crucial in maintaining cellular iron homeostasis as a large number of mRNAs connected to iron storage and metabolism including ferritin, mitochondrial aconitase, succinate dehydrogenase-iron protein, erythroid 5-aminolevulinate synthetase (eALAS), and an iron-exportin molecule named ferroportin (FPN1) have their expression modulated by this system. When cellular iron levels are low, IRP1 and IRP2 bind the IRE and block translation of the downstream ORF. When intracellular iron levels are high, the RNA binding activity of both IRPs is reduced (Figure 2(a)). IREs tend to be positioned close to the cap, which causes a steric inhibition of the binding of 40S ribosomal subunits to the transcript. When located distant to the cap, rather than affecting 40S recruitment, the IRE-IRP complex blocks ribosomal scanning (reviewed in [26]). An interesting bypass of the IRE/IRP mechanism can be observed in iron-starved duodenal and erythroid precursor cells. An upstream promoter is used to generate FPN1 pre-mRNAs containing one more exon that is connected by alternative splicing to a splice acceptor in the 3′ of the IRE. A mature FPN1 transcript containing the same open reading frame is generated; however, the 5′ UTR does not contain the IRE [27]. Therefore, these cells express the alternative FPN1 isoform in an iron-independent manner [27, 28]. Mutations affecting IREs can lead to diseases. This is the case of hereditary hyperferritinemia-cataract syndrome (HHCS), a genetic autosomal dominant disorder in which aggregation and crystallization of ferritin in the lens leads to bilateral cataracts [29].


Before It Gets Started: Regulating Translation at the 5' UTR.

Araujo PR, Yoon K, Ko D, Smith AD, Qiao M, Suresh U, Burns SC, Penalva LO - Comp. Funct. Genomics (2012)

Translational regulation by RNA binding proteins. (a) In iron-deficient cells, IRPs bind to the IRE localized in the 5′ UTR of ferritin mRNA, blocking its translation. Once cellular iron levels increase, a complex containing Fe binds to IRPs. Thus, these proteins are allosterically modified, which reduces IRP-IRE binding and allows the translation of ferritin mRNAs. (b) msl-2 gene regulation in females flies. After transcription in the nucleus, SXL specifically binds to intronic U-rich regions of msl-2 pre-mRNA and inhibits the intron removal (1). In the cytoplasm, SXL binds to the same elements localized now in the 5′ UTR of mature msl-2 mRNA, enhances the translation initiation of a upstream ORF (2), and prevents the main ORF translation (3). The regulatory elements in the 3′ UTR of msl-2 mRNA were not represented.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368165&req=5

fig2: Translational regulation by RNA binding proteins. (a) In iron-deficient cells, IRPs bind to the IRE localized in the 5′ UTR of ferritin mRNA, blocking its translation. Once cellular iron levels increase, a complex containing Fe binds to IRPs. Thus, these proteins are allosterically modified, which reduces IRP-IRE binding and allows the translation of ferritin mRNAs. (b) msl-2 gene regulation in females flies. After transcription in the nucleus, SXL specifically binds to intronic U-rich regions of msl-2 pre-mRNA and inhibits the intron removal (1). In the cytoplasm, SXL binds to the same elements localized now in the 5′ UTR of mature msl-2 mRNA, enhances the translation initiation of a upstream ORF (2), and prevents the main ORF translation (3). The regulatory elements in the 3′ UTR of msl-2 mRNA were not represented.
Mentions: The best characterized example of RBP-mediated regulation involving 5′ UTRs is provided by the iron regulatory proteins (IRP 1 and 2). These proteins recognize a highly conserved stem loop structure with circa 30 nucleotides, known as the iron response element (IRE). The most important features include a hexanucleotide loop with the sequence CAGYCX (Y = U or A; X = U, C, or A) and a 5 bp upper stem that is separated from a lower stem of variable length by an unpaired cytosine. This regulation is crucial in maintaining cellular iron homeostasis as a large number of mRNAs connected to iron storage and metabolism including ferritin, mitochondrial aconitase, succinate dehydrogenase-iron protein, erythroid 5-aminolevulinate synthetase (eALAS), and an iron-exportin molecule named ferroportin (FPN1) have their expression modulated by this system. When cellular iron levels are low, IRP1 and IRP2 bind the IRE and block translation of the downstream ORF. When intracellular iron levels are high, the RNA binding activity of both IRPs is reduced (Figure 2(a)). IREs tend to be positioned close to the cap, which causes a steric inhibition of the binding of 40S ribosomal subunits to the transcript. When located distant to the cap, rather than affecting 40S recruitment, the IRE-IRP complex blocks ribosomal scanning (reviewed in [26]). An interesting bypass of the IRE/IRP mechanism can be observed in iron-starved duodenal and erythroid precursor cells. An upstream promoter is used to generate FPN1 pre-mRNAs containing one more exon that is connected by alternative splicing to a splice acceptor in the 3′ of the IRE. A mature FPN1 transcript containing the same open reading frame is generated; however, the 5′ UTR does not contain the IRE [27]. Therefore, these cells express the alternative FPN1 isoform in an iron-independent manner [27, 28]. Mutations affecting IREs can lead to diseases. This is the case of hereditary hyperferritinemia-cataract syndrome (HHCS), a genetic autosomal dominant disorder in which aggregation and crystallization of ferritin in the lens leads to bilateral cataracts [29].

Bottom Line: Translation regulation plays important roles in both normal physiological conditions and diseases states.This regulation requires cis-regulatory elements located mostly in 5' and 3' UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity.In this paper, we discuss important aspects of 5' UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

View Article: PubMed Central - PubMed

Affiliation: Greehey Children's Cancer Research Institute, UTHSCSA, San Antonio, TX 78229-3900, USA.

ABSTRACT
Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5' and 3' UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5' UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

No MeSH data available.


Related in: MedlinePlus