Dujardin Gwendal, Daguenet Élisabeth, Bernard Delphine G, Flodrops Marion, Durand Stéphanie, Chauveau Aurélie, El Khoury Flaria, Le Jossic-Corcos Catherine, Corcos Laurent
Centre de Regulació Genòmica (CRG), the Barcelona Institute of Science and Technology, Barcelone, Espagne.
Inserm U1078-ECLA, Université de Bretagne Occidentale, Institut Brestois en Santé Agro Matière (IBSAM), Faculté de médecine, 22, avenue Camille Desmoulins, 29200 Brest, France.
Med Sci (Paris). 2016 Dec;32(12):1103-1110. doi: 10.1051/medsci/20163212014. Epub 2017 Jan 3.
Pre-mRNA splicing is an obligatory step required to assemble the vast majority of mRNAs in eukaryotes. In humans, each gene gives rise to at least two transcripts, with an average 6-8 spliced transcripts per gene. Pre-mRNA splicing is not unequivocal. Variations may occur, such that splicing can become alternative, thereby participating in increasing protein variability and restricting the gap that exists between the relatively low number of genes - between 20,000 and 25,000 in humans - and the much higher number of distinct proteins - at least 100,000. In addition, although alternative pre-mRNA splicing often fulfils cell-specific needs, many aberrant splicing events can happen and lead to either hereditary or acquired diseases such as neurodegenerative diseases or cancers. In those cases, alternative splicing events may serve as disease-associated markers, or even as targets for corrective approaches. In this review, we will summarize the main aspects of regulated alternative splicing. We will present the spliceosome, a large ribonucleoprotein complex that orchestrates the splicing reactions and that was recently identified as a preferential target for mutations in several pathologies. We shall discuss some spliceosome-associated defects linked to either cis (i.e on the DNA) or trans (e.g. in proteins) alterations of splicing machinery, like those that have been reported in genetic or acquired diseases.
前体mRNA剪接是真核生物中组装绝大多数mRNA所必需的一个步骤。在人类中，每个基因至少产生两种转录本，每个基因平均有6 - 8个剪接转录本。前体mRNA剪接并非是明确无误的。可能会出现变异，使得剪接可以成为选择性的，从而参与增加蛋白质的多样性，并缩小人类中相对较少的基因数量（20000到25000个）与数量多得多的不同蛋白质（至少100000种）之间存在的差距。此外，尽管选择性前体mRNA剪接通常满足细胞特异性需求，但许多异常剪接事件可能发生并导致遗传性或获得性疾病，如神经退行性疾病或癌症。在这些情况下，选择性剪接事件可能作为疾病相关标志物，甚至作为纠正方法的靶点。在本综述中，我们将总结调控选择性剪接的主要方面。我们将介绍剪接体，这是一种大型核糖核蛋白复合体，它协调剪接反应，并且最近被确定为几种病理学中突变的优先靶点。我们将讨论一些与剪接机制的顺式（即DNA上的）或反式（例如蛋白质中的）改变相关的剪接体相关缺陷，就像在遗传或获得性疾病中所报道的那些。
