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Molecular mechanisms of eukaryotic pre-mRNA 3' end processing regulation.

Millevoi S, Vagner S - Nucleic Acids Res. (2009)

Bottom Line: It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units.A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events.Here, we review the eukaryotic 3' end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3' end processing regulation by proposing several overlapping models of regulation.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U563, Toulouse, F-31000, France. stefania.millevoi@inserm.fr

ABSTRACT
Messenger RNA (mRNA) 3' end formation is a nuclear process through which all eukaryotic primary transcripts are endonucleolytically cleaved and most of them acquire a poly(A) tail. This process, which consists in the recognition of defined poly(A) signals of the pre-mRNAs by a large cleavage/polyadenylation machinery, plays a critical role in gene expression. Indeed, the poly(A) tail of a mature mRNA is essential for its functions, including stability, translocation to the cytoplasm and translation. In addition, this process serves as a bridge in the network connecting the different transcription, capping, splicing and export machineries. It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units. A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events. Here, we review the eukaryotic 3' end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3' end processing regulation by proposing several overlapping models of regulation.

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The 3′ end processing at single or multiple pA signals and its interconnections with the splicing/transcription machineries. Alternative 3′ end processing occurs through the selection of pA signals in the same exon or in different alternative exons. The physical and functional interdependence between 3′ end processing and transcription/splicing is represented by red/green dotted lines.
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Figure 1: The 3′ end processing at single or multiple pA signals and its interconnections with the splicing/transcription machineries. Alternative 3′ end processing occurs through the selection of pA signals in the same exon or in different alternative exons. The physical and functional interdependence between 3′ end processing and transcription/splicing is represented by red/green dotted lines.

Mentions: Although cleavage and polyadenylation can be studied as isolated processes in vitro, mRNA 3′ end formation in vivo is an integral component of the coupled network in which the different machines carrying out separate steps of the gene expression pathway are tethered to each other to form a gene expression factory. In this network, 3′ end processing cross-talks with the transcription and splicing steps to optimize the efficiency and specificity of each enzymatic reaction (Figure 1) (1). The physical interconnections between the splicing/transcription and 3′ end processing machineries create a strong functional interdependence. Indeed, 3′ end polyadenylation factors (or pA factors, including factors involved in both cleavage and polyadenylation) and sequence elements of the poly(A) signal modulate transcription termination (2–5) and, in turn, transcription factors/activators affect processing at the poly(A) signal (6–9). The phosphorylated carboxyl-terminal domain (CTD) of pol II also plays a major role in this coupling network by serving as a gathering/delivering platform of pA factors and is an integral component of the 3′ end processing complex (10,11). The functional interdependence between splicing and 3′ end processing is mediated by the molecular link between splicing factors bound at the last intron 3′ splice site and pA factors associated to the poly(A) signal in the terminal exon [(12–16) and references inside] and contributes to define the last exon of a pre-mRNA (17).Figure 1.


Molecular mechanisms of eukaryotic pre-mRNA 3' end processing regulation.

Millevoi S, Vagner S - Nucleic Acids Res. (2009)

The 3′ end processing at single or multiple pA signals and its interconnections with the splicing/transcription machineries. Alternative 3′ end processing occurs through the selection of pA signals in the same exon or in different alternative exons. The physical and functional interdependence between 3′ end processing and transcription/splicing is represented by red/green dotted lines.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874999&req=5

Figure 1: The 3′ end processing at single or multiple pA signals and its interconnections with the splicing/transcription machineries. Alternative 3′ end processing occurs through the selection of pA signals in the same exon or in different alternative exons. The physical and functional interdependence between 3′ end processing and transcription/splicing is represented by red/green dotted lines.
Mentions: Although cleavage and polyadenylation can be studied as isolated processes in vitro, mRNA 3′ end formation in vivo is an integral component of the coupled network in which the different machines carrying out separate steps of the gene expression pathway are tethered to each other to form a gene expression factory. In this network, 3′ end processing cross-talks with the transcription and splicing steps to optimize the efficiency and specificity of each enzymatic reaction (Figure 1) (1). The physical interconnections between the splicing/transcription and 3′ end processing machineries create a strong functional interdependence. Indeed, 3′ end polyadenylation factors (or pA factors, including factors involved in both cleavage and polyadenylation) and sequence elements of the poly(A) signal modulate transcription termination (2–5) and, in turn, transcription factors/activators affect processing at the poly(A) signal (6–9). The phosphorylated carboxyl-terminal domain (CTD) of pol II also plays a major role in this coupling network by serving as a gathering/delivering platform of pA factors and is an integral component of the 3′ end processing complex (10,11). The functional interdependence between splicing and 3′ end processing is mediated by the molecular link between splicing factors bound at the last intron 3′ splice site and pA factors associated to the poly(A) signal in the terminal exon [(12–16) and references inside] and contributes to define the last exon of a pre-mRNA (17).Figure 1.

Bottom Line: It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units.A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events.Here, we review the eukaryotic 3' end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3' end processing regulation by proposing several overlapping models of regulation.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U563, Toulouse, F-31000, France. stefania.millevoi@inserm.fr

ABSTRACT
Messenger RNA (mRNA) 3' end formation is a nuclear process through which all eukaryotic primary transcripts are endonucleolytically cleaved and most of them acquire a poly(A) tail. This process, which consists in the recognition of defined poly(A) signals of the pre-mRNAs by a large cleavage/polyadenylation machinery, plays a critical role in gene expression. Indeed, the poly(A) tail of a mature mRNA is essential for its functions, including stability, translocation to the cytoplasm and translation. In addition, this process serves as a bridge in the network connecting the different transcription, capping, splicing and export machineries. It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units. A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events. Here, we review the eukaryotic 3' end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3' end processing regulation by proposing several overlapping models of regulation.

Show MeSH