Mechanisms and Regulation of Alternative Pre-mRNA Splicing.
Mechanisms and Regulation of Alternative Pre-mRNA Splicing.
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DOI：
10.1146/annurev-biochem-060614-034316
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发表时间：
2015
影响因子：
16.6
通讯作者：
Rio DC
中科院分区：
文献类型：
--
作者：
Lee Y;Rio DC
前体信使RNA（pre-mRNA）剪接是基因表达的转录后调控中的关键步骤，为具有有限基因数目的真核生物的功能蛋白质组提供显著扩增。分裂的真核基因含有插入序列或内含子破坏蛋白质编码外显子，内含子的去除是通过重复组装一个大的和高度动态的核糖核蛋白复合物（称为剪接体）而发生的，剪接体由五个小的核核糖核蛋白颗粒U1，U2，U4/U6和U 5组成。在过去的10年中，生物化学研究允许分离以及组成，功能和结构分析的剪接复合物在不同的阶段，沿着剪接体周期。人类基因平均包含8个外显子和7个内含子，平均产生3种或更多种选择性剪接的mRNA亚型。最近的高通量测序研究表明，100%的人类基因产生至少两种替代的mRNA亚型。选择性剪接的机制包括剪接因子与称为沉默子或增强子的调控位点的RNA-蛋白质相互作用、RNA-RNA碱基配对相互作用或可改变或决定剪接模式的基于染色质的效应。致病突变通常发生在内含子边界附近的剪接位点或外显子或内含子RNA调节沉默子或增强子元件中，以及编码剪接因子的基因中。总之，这些研究提供了关于剪接体组装、动力学和催化如何发生的机理性见解;选择性剪接如何被调节和演变;以及剪接如何被导致疾病状态的顺式和反式作用突变破坏。这些发现使剪接体成为小分子、反义和基因组编辑治疗干预的有吸引力的新靶点。
Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the functional proteome of eukaryotic organisms with limited gene numbers. Split eukaryotic genes contain intervening sequences or introns disrupting protein-coding exons, and intron removal occurs by repeated assembly of a large and highly dynamic ribonucleoprotein complex termed the spliceosome, which is composed of five small nuclear ribonucleoprotein particles, U1, U2, U4/U6, and U5. Biochemical studies over the past 10 years have allowed the isolation as well as compositional, functional, and structural analysis of splicing complexes at distinct stages along the spliceosome cycle. The average human gene contains eight exons and seven introns, producing an average of three or more alternatively spliced mRNA isoforms. Recent high-throughput sequencing studies indicate that 100% of human genes produce at least two alternative mRNA isoforms. Mechanisms of alternative splicing include RNA–protein interactions of splicing factors with regulatory sites termed silencers or enhancers, RNA–RNA base-pairing interactions, or chromatin-based effects that can change or determine splicing patterns. Disease-causing mutations can often occur in splice sites near intron borders or in exonic or intronic RNA regulatory silencer or enhancer elements, as well as in genes that encode splicing factors. Together, these studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by cis- and trans-acting mutations leading to disease states. These findings make the spliceosome an attractive new target for small-molecule, antisense, and genome-editing therapeutic interventions.