Abstract
Transcription termination of nearly all protein-coding genes in mammals requires 3’ end processing by a multiprotein complex that will cleave and polyadenylate the messenger RNA precursor. Because a variety of enzyme complexes intervene, 3’ end processing was thought to be fundamentally complex and subject to a multitude of regulatory effects. The possibility to select just one out of several polyadenylation sites, in particular, has caused much questioning and speculation. What appear to be separate mechanisms however can be combined into a defined set of rules, allowing for a relatively simple interpretation of 3’ end processing. Ultimately, readiness of the terminal exon splice site determines when a transcript reaches the maturity to select a nearby polyadenylation signal. Transcriptional pausing then acts in concert, extending the timeframe during which the transcription complex is close to polyadenylation sites. Since RNA polymerase pausing is governed by the same type of sequences in bacteria and metazoans, mammalian transcription termination resembles its prokaryote counterpart more than generally thought.
Highlights
Most genes in mammals have evolved into large transcription units, bearing relatively small protein-coding exons separated by very large introns
The same process in mammals generally requires a combination of enzyme complexes, in particular for protein-coding genes transcribed by RNA Polymerase II (Pol II)
DIDO mutation causes a redistribution of splicing efficiencies due to differential recruitment of the general splicing facilitator SFPQ
Summary
Most genes in mammals have evolved into large transcription units, bearing relatively small protein-coding exons separated by very large introns These genes span 10 to 15 kilobases on average, but occasionally reach a size of more than 1000 kilobases. Individual genes must be functionally separated, which implies that transcription termination at the 3’ end is strictly controlled and should be coordinated with other aspects of messenger RNA production. The same process in mammals generally requires a combination of enzyme complexes, in particular for protein-coding genes transcribed by RNA Polymerase II (Pol II). In agreement with the proposed requirements for 3’ end processing, RNA and chromatin immunoprecipitation (CHIP) sequencing have shown frequent Pol II pausing in terminal exons and downstream of genes (Carrillo Oesterreich et al, 2010; Cortazar et al, 2019). The reasons why and where Pol II pauses might been answered but the way how it does so still need explaining
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