The exon junction complex: A splicing factor for long intron containing transcripts? (original) (raw)
Related papers
Embracing the complexity of pre-mRNA splicing
Cell Research, 2010
Pre-mRNA splicing is a fundamental process required for the expression of most metazoan genes. It is carried out by the spliceosome, which catalyzes the removal of non-coding intronic sequences to assemble exons into mature mRNAs prior to export and translation. Defects in splicing lead to many human genetic diseases , and splicing mutations in a number of genes involved in growth control have been implicated in multiple types of cancer . Given the complexity of higher eukaryotic genes and the relatively low level of splice-site conservation, the precision of the splicing machinery in recognizing and pairing splice sites is remarkable. Introns ranging in size from less than 100 up to 100 000 bases are removed efficiently. At the same time, a large number of alternative splicing events are observed between different cell types, developmental stages, and during other biological processes. Of the approximately 25 000 genes encoded by the human genome [3], more than 90% are believed to produce transcripts that are alternatively spliced . Thus, alternative splicing of pre-mRNAs can lead to the production of multiple protein isoforms from a single pre-mRNA, significantly enriching the proteomic diversity of higher eukaryotic organisms . Because regulation of this process can determine the timing and location in which a particular protein isoform is produced, changes in alternative splicing patterns modulate many cellular activities. This extensive alternative splicing implies a significant flexibility of the spliceosome to identify and process exons within a given pre-mRNA.
Regulation of splicing: The importance of being translatable
RNA, 2004
RNA sequences that conform to the consensus sequence of 5 splice sites but are not used for splicing occur frequently in protein coding genes. Mutational analyses have shown that suppression of splicing at such latent sites may be dictated by the necessity to maintain an open reading frame in the mRNA. Here we show that stop codon frequency in introns having latent 5 splice sites is significantly greater than that of introns lacking such sites and significantly greater than the expected occurrence by chance alone. Both observations suggest the occurrence of a general mechanism that recognizes the mRNA reading frame in the context of pre-mRNA.
Molecular Cell, 2006
The splicing machinery associates with genes to facilitate efficient cotranscriptional mRNA processing. We have mapped these associations by genome localization analysis to ascertain how splicing is achieved and regulated on a system-wide scale. Our data show that factors important for intron recognition sample nascent mRNAs and are retained specifically at intron-containing genes via RNA-dependent interactions. Spliceosome assembly proceeds cotranscriptionally but completes posttranscriptionally in most cases. Some intron-containing genes were not bound by the spliceosome, including several developmentally regulated genes. On this basis, we predicted and verified regulated splicing and observed a role for nuclear mRNA surveillance in monitoring those events. Finally, we present evidence that cotranscriptional processing events determine the recruitment of specific mRNA export factors. Broadly, our results provide mechanistic insights into the coordinated regulation of transcription, mRNA processing, and nuclear export in executing complex gene expression programs.
Regulated pre-mRNA splicing: The ghostwriter of the eukaryotic genome
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2012
Intron removal is at the heart of mRNA synthesis. It is mediated by one of the cell's largest complexes, the spliceosome. Yet, the fundamental chemistry involved is simple. In this review we will address how the spliceosome acts in diverse ways to optimize gene expression in order to meet the cell's needs. This is done largely by regulating the splicing of key transcripts encoding products that control gene expression pathways. This widespread role is evident even in the yeast Saccharomyces cerevisiae, where many introns appear to have been lost; yet how this control is being achieved is known only in a few cases. Here we explore the relevant examples and posit hypotheses whereby regulated splicing fine-tunes gene expression pathways to maintain cell homeostasis. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.
Alternative pre-mRNA splicing: Theory and protocols
Recherche, 2012
. Exons and introns are defined by the 5 0 and 3 0 splice sites, which follow the degenerate sequences YAG/guragu and yyyyyyyyyyynyag/G. . The genome contains more pseudoexons than authentic exons. . Exon recognition depends on the interplay of multiple splicing regulatory elements, that can be either intronic or exonic, and act as either enhancers or silencers (ESE, ESS, ISE, ISS). . Pre-mRNA splicing is coupled to transcription, and is influenced by promoter type, polymerase speed, histone modifications, and polyadenylation signals. . All of these factors contribute to the combinatorial control of splice site selection.
Serine-arginine (SR)-rich splicing factors have an exon-independent function in pre-mRNA splicing
Proceedings of the National Academy of Sciences, 1999
Two distinct functions have been proposed for the serine-arginine (SR)-rich family of splicing factors. First, SR proteins are essential splicing factors and are thought to function by mediating protein-protein interactions within the intron during spliceosome assembly. Second, SR proteins bind to exonic enhancer sequences and recruit spliceosome components to adjacent introns. The latter activity is required for splice-site recognition and alternative splicing. Until now it has not been possible to determine whether the requirement for SR proteins in the basic splicing reaction is a secondary consequence of their exon-dependent recruitment function. Here we show that RNA substrates containing only 1 nt of exon sequence can undergo the first step of the splicing reaction in vitro and that this activity requires SR proteins. Thus, we provide direct evidence that SR proteins have both exon-independent and exon-dependent functions in pre-mRNA splicing.