3′ end mRNA processing: molecular mechanisms and implications for health and disease

Danckwardt, Sven; Hentze, Matthias W.; Kulozik, Andreas E.

doi:10.1038/sj.emboj.7601932

Cited by 251 publications

(282 citation statements)

References 200 publications

(352 reference statements)

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“…In the other two cases the deletion extended into the 3¢-UTR, and may therefore extend into downstream genes. Patient 8 presented with dysmorphic features consistent with a diagnosis of TCS, and was shown to have a deletion of exons [23][24][25][26], that removes the C-terminal region of treacle important for localisation to the nucleolus. Array CGH analysis suggested that the deletion did not extend into the downstream CD74 gene.…”

Section: Discussionmentioning

confidence: 99%

“…This is a sequence motif recognised by RNA-binding factors and is essential for transcriptional termination and efficient polyadenylation of mRNAs and release of the polyadenylated mRNA for export from the nucleus. 26 Mutations affecting a polyadenylation signal and the secondary structure of the 3¢-UTR of mRNA have been shown to cause translation de-regulation 27 and have been reported in other diseases. [28][29][30][31] It is therefore predicted that deletion of this signal in TCOF1 would lead to reduced accumulation of treacle, consistent with a mechanism of haploinsufficiency in TCS.…”

Section: Discussionmentioning

confidence: 99%

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Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

et al. 2012

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Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion. A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity. The majority of the pathogenic sequence changes were found to predict premature protein termination, however, four novel missense changes in the LIS1 homology motif at the 5¢ end of the gene were identified. The partial gene deletions of different sizes represent B5.2% of all the pathogenic TCOF1 mutations identified, indicating that gene rearrangements account for a significant proportion of TCS cases. This is the first report of gene rearrangements resulting in TCS. These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis, a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

et al. 2012

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“…In ;1% of Caucasians (myself included), this sequence is mutated to CA, causing a mild thrombophilia phenotype. This is due to a twofold increase in prothrombin gene expression as a result of the acquisition of a more efficient PAS (Gehring et al 2001;Danckwardt et al 2008). These defining experiments for mRNA PAS were focused on mammalian mRNA.…”

Section: Polyadenylation Signals and 39 Noncoding Rna (Ncrna) Sequencesmentioning

confidence: 99%

Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

519

486

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Polyadenylation [poly(A)] signals (PAS) are a defining feature of eukaryotic protein-coding genes. The central sequence motif AAUAAA was identified in the mid1970s and subsequently shown to require flanking, auxiliary elements for both 39-end cleavage and polyadenylation of premessenger RNA (pre-mRNA) as well as to promote downstream transcriptional termination. More recent genomic analysis has established the generality of the PAS for eukaryotic mRNA. Evidence for the mechanism of mRNA 39-end formation is outlined, as is the way this RNA processing reaction communicates with RNA polymerase II to terminate transcription. The widespread phenomenon of alternative poly(A) site usage and how this interrelates with pre-mRNA splicing is then reviewed. This shows that gene expression can be drastically affected by how the message is ended. A central theme of this review is that while genomic analysis provides generality for the importance of PAS selection, detailed mechanistic understanding still requires the direct analysis of specific genes by genetic and biochemical approaches.

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“…Cleavage and polyadenylation can be uncoupled in vitro but in vivo they are connected with each other and with transcription termination. Defects in 3′-end processing have also been associated with several diseases in humans (9), but this process may be even more critical in yeast that has shorter intergenic regions and much rarer alternative splicing (10,11). In this organism, efficient mRNA transport is mostly dependent on polyadenylation rather than splicing.…”

mentioning

confidence: 99%

Structural and biochemical analysis of the assembly and function of the yeast pre-mRNA 3′ end processing complex CF I

Barnwal

Lee

Moore

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The accuracy of the 3′-end processing by cleavage and polyadenylation is essential for mRNA biogenesis and transcription termination. In yeast, two poorly conserved neighboring elements upstream of cleavage sites are important for accuracy and efficiency of this process. These two RNA sequences are recognized by the RNA binding proteins Hrp1 and Rna15, but efficient processing in vivo requires a bridging protein (Rna14), which forms a stable dimer of heterodimers with Rna15 to stabilize the RNA-protein complex. We earlier reported the structure of the ternary complex of Rna15 and Hrp1 bound to the RNA processing element. We now report the use of solution NMR to study the interaction of Hrp1 with the Rna14-Rna15 heterodimer in the presence and absence of 3′-end processing signals. By using methyl selective labeling on Hrp1, in vivo activity and pull-down assays, we were able to study this complex of several hundred kDa, identify the interface within Hrp1 responsible for recruitment of Rna14 and validate the functional significance of this interaction through structure-driven mutational analysis.mRNA processing | mRNA transport | protein-RNA | methyl-TROSY | modeling E ukaryotic messenger RNA precursors (pre-mRNA) undergo extensive cotranscriptional processing before their transport to the cytoplasm and subsequent translation (1, 2). The processing events include 5′-end capping, splicing to remove intronic sequences and cleavage and polyadenylation at the 3′-end (3, 4). Correct 3′-end processing is necessary for mRNA biogenesis and transcription termination, preserves RNAs from degradation (5), promotes its export to the cytoplasm (6), enhances translation (7) and promotes transcriptional activation (4, 8). Cleavage and polyadenylation can be uncoupled in vitro but in vivo they are connected with each other and with transcription termination. Defects in 3′-end processing have also been associated with several diseases in humans (9), but this process may be even more critical in yeast that has shorter intergenic regions and much rarer alternative splicing (10, 11). In this organism, efficient mRNA transport is mostly dependent on polyadenylation rather than splicing.In yeast, the 3′-end processing reaction is executed by a complex machine containing more than 20 proteins (4) which share significant similarities with human 3′-end processing proteins. The entire yeast 3′-end processing complex is divided into two subcomplexes, called cleavage factor I (CF I) and cleavage and polyadenylation factor (CPF) (4). CF I binds to the pre-mRNA upstream of the cleavage signal within the pre-mRNA, whereas CPF binds at the cleavage site as well as upstream and downstream of the cleavage site. Several sequences within yeast pre-mRNAs, which are surprisingly poorly conserved, direct the recruitment of cleavage and polyadenylation factors (12, 13). In the 5′-3′ direction, they include AU-rich efficiency element (EE) responsible for polyadenylation efficiency; A-rich positioning element (PE) critical for precise 3′-end processing; t...

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3′ end mRNA processing: molecular mechanisms and implications for health and disease

Cited by 251 publications

References 200 publications

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

Ending the message: poly(A) signals then and now

Structural and biochemical analysis of the assembly and function of the yeast pre-mRNA 3′ end processing complex CF I

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