哺乳动物细胞mRNA剪接调控的分子机制

mRNA的可变剪接是指一个单一的mRNA前体(pre-mRNA)经过不同的剪接加工方式生成多种mRNA变异体(variants)的过程,这些变异体最终可以编码合成具有不同结构和功能的蛋白质。在过去的10多年中,大量数据表明,可变剪接是增加转录组和蛋白质组多样性的重要资源,也是调控哺乳动物细胞基因表达的重要步骤。可变剪接具有高度的组织与发育阶段特异性,并受到外界信号的控制。剪接调控的紊乱与疾病的发生发展密切相关。该文将对哺乳动物细胞mRNA剪接调控的分子机制进行阐述。     

Regulation of mammalian pre-mRNA splicing

In eukaryotes, most protein-coding genes contain introns which are removed by precursor messenger RNA (pre-mRNA) splicing. Alternative splicing is a process by which multiple messenger RNAs (mRNAs) are generated from a single pre-mRNA, resulting in functionally distinct proteins. Recent genome-wide analyses of alternative splicing indicated that in higher eukaryotes alternative splicing is an important mechanism that generates proteomic complexity and regulates gene expression. Mis-regulation of splicing causes a wide range of human diseases. This review describes the current understanding of pre-mRNA splicing and the mechanisms that regulate mammalian pre-mRNA splicing. It also discusses emerging directions in the field of alternative splicing. Supported by the Program of “one Hundred Talented people” of the Chinese Academy of Sciences.     

Plant serine/arginine-rich proteins and their role in pre-mRNA splicing

Pre-messenger RNA (pre-mRNA) splicing, a process by which mature mRNAs are generated by excision of introns and ligation of exons, is an important step in the regulation of gene expression in all eukaryotes. Selection of alternative splice sites in a pre-mRNA generates multiple mRNAs from a single gene that encode structurally and functionally distinct proteins. Alternative splicing of pre-mRNAs contributes greatly to the proteomic complexity of plants and animals and increases the coding potential of a genome. However, the mechanisms that regulate constitutive and alternative splicing of pre-mRNA are not understood in plants. A serine/arginine-rich (SR) family of proteins is implicated in constitutive and alternative splicing of pre-mRNAs. Here I review recent progress in elucidating the roles of serine/arginine-rich proteins in pre-mRNA splicing.     

Unbalanced alternative splicing and its significance in cancer

Alternative pre-mRNA splicing leads to distinct products of gene expression in development and disease. Antagonistic splice variants of genes involved in differentiation, apoptosis, invasion and metastasis often exist in a delicate equilibrium that is found to be perturbed in tumours. In several recent examples, splice variants that are overexpressed in cancer are expressed as hyper-oncogenic proteins, which often correlate with poor prognosis, thus suggesting improved diagnosis and follow up treatment. Global gene expression technologies are just beginning to decipher the interplay between alternatively spliced isoforms and protein-splicing factors that will lead to identification of the mutations in these trans-acting factors responsible for pathogenic alternative splicing in cancer.     

染色质结构与mRNA可变剪接

mRNA的可变剪接(alternative splicing)是一种由一个mRNA前体(pre-mRNA)通过不同的剪接方式产生多个mRNA变异体(variants)的RNA加工过程。在过去很长一段时间里,人们认为mRNA剪接过程是独立于转录过程的一个转录后RNA加工过程。然而,越来越多的实验证明mRNA剪接在很大程度上是与转录偶联发生的。因此,剪接调控会受到与转录相关因素的调控。本文将对染色质与mRNA剪接调控的相关性和染色质结构调控可变剪接的分子机制进行阐述。     

The Drosophila Splicing Factor PSI Is Phosphorylated by Casein Kinase II and Tousled-Like Kinase

Alternative splicing of pre-mRNA is a highly regulated process that allows cells to change their genetic informational output. These changes are mediated by protein factors that directly bind specific pre-mRNA sequences. Although much is known about how these splicing factors regulate pre-mRNA splicing events, comparatively little is known about the regulation of the splicing factors themselves. Here, we show that the Drosophila splicing factor P element Somatic Inhibitor (PSI) is phosphorylated at at least two different sites by at minimum two different kinases, casein kinase II (CK II) and tousled-like kinase (tlk). These phosphorylation events may be important for regulating protein-protein interactions involving PSI. Additionally, we show that PSI interacts with several proteins in Drosophila S2 tissue culture cells, the majority of which are splicing factors.     

Control of alternative pre-mRNA splicing by Ca(++) signals

Alternative pre-mRNA splicing is a common way of gene expression regulation in metazoans. The selective use of specific exons can be modulated in response to various manipulations that alter Ca(++) signals, particularly in neurons. A number of splicing factors have also been found to be controlled by Ca(++) signals. Moreover, pre-mRNA elements have been identified that are essential and sufficient to mediate Ca(++)-regulated splicing, providing model systems for dissecting the involved molecular components. In neurons, this regulation likely contributes to the fine-tuning of neuronal properties.     

可变剪接在神经发育过程中对生物学功能的影响

可变剪接(alternative splicing)发生在前体m RNA向成熟m RNA的转换过程中,是转录后表达调控和产生蛋白质多样性的重要机制。可变剪接在真核生物中普遍存在,神经系统发育作为一个极其复杂且严密的过程,可变剪接对它的影响更明显。近年来,一些参与神经发育的可变剪接事件已经得到一定程度的验证,可以得知它的发生影响了突触生长、突触传递和神经干细胞的形成等生物学功能。同时,当可变剪接的模式发生改变时往往也会造成神经系统的功能异常。因此,本文就可变剪接的机制进行了简短的介绍,探索其在神经发育及神经疾病中的作用,并简单总结了相关数据库。     

Understanding alternative splicing: towards a cellular code

In violation of the 'one gene, one polypeptide' rule, alternative splicing allows individual genes to produce multiple protein isoforms - thereby playing a central part in generating complex proteomes. Alternative splicing also has a largely hidden function in quantitative gene control, by targeting RNAs for nonsense-mediated decay. Traditional gene-by-gene investigations of alternative splicing mechanisms are now being complemented by global approaches. These promise to reveal details of the nature and operation of cellular codes that are constituted by combinations of regulatory elements in pre-mRNA substrates and by cellular complements of splicing regulators, which together determine regulated splicing pathways.     

Maps, codes, and sequence elements: can we predict the protein output from an alternatively spliced locus?

Alternative splicing choices are governed by splicing regulatory protein interactions with splicing silencer and enhancer elements present in the pre-mRNA. However, the prediction of these choices from genomic sequence is difficult, in part because the regulators can act as either enhancers or silencers. A recent study describes how for a particular neuronal splicing regulatory protein, Nova, the location of its binding sites is highly predictive of the protein's effect on an exon's splicing.     

Neuronal regulation of pre-mRNA splicing by polypyrimidine tract binding proteins,PTBP1 and PTBP2

Alternative splicing patterns are regulated by RNA binding proteins that assemble onto each pre-mRNA to form a complex RNP structure. The polypyrimidine tract binding protein, PTB, has served as an informative model for understanding how RNA binding proteins affect spliceosome assembly and how changes in the expression of these proteins can control complex programs of splicing in tissues. In this review, we describe the mechanisms of splicing regulation by PTB and its function, along with its paralog PTBP2, in neuronal development.     

Neuronal regulation of pre-mRNA splicing by polypyrimidine tract binding proteins, PTBP1 and PTBP2

Alternative splicing patterns are regulated by RNA binding proteins that assemble onto each pre-mRNA to form a complex RNP structure. The polypyrimidine tract binding protein, PTB, has served as an informative model for understanding how RNA binding proteins affect spliceosome assembly and how changes in the expression of these proteins can control complex programs of splicing in tissues. In this review, we describe the mechanisms of splicing regulation by PTB and its function, along with its paralog PTBP2, in neuronal development.