Regulatory Mechanisms Controlling Alternative Splicing

人类基因组有大约21000个基因；基因编码蛋白质，但基因本身是分裂的，将蛋白质编码区组织成称为“外显子”的离散区块。在每个细胞中，只有一部分基因在被称为“转录”的过程中转录成RNA。然后，这些RNA被用来指导指定序列的蛋白质的生产。在基因转录成RNA之后，外显子就被缝合在一起，这一过程被称为“剪接”。剪接过程还可以将外显子以不同的顺序缝合在一起，从而产生具有不同序列和功能的蛋白质。细胞内独特的一组蛋白质是由调控转录和剪接的控制过程定义的，以选择使用哪些基因和外显子的哪个顺序。这种调节是细胞修改其蛋白质库以适应环境的主要手段。最近，科学家们了解到，剪接和转录不是独立调控的，而是由尚不清楚的蛋白质和过程共同调控的。我们研究了两种密切相关的人类蛋白质，它们既可以调节外显子的顺序，也可以调节转录水平。这些蛋白质是酶，称为“激酶”，它将一个磷酸分子添加到其他蛋白质的位点上，从而改变它们的功能。在我们的实验中，我们已经确定了其他几种与这些激酶相互作用的蛋白质，从而提供了关于这些激酶如何执行其功能的信息。在我们的研究中，我们将描述这两种激酶及其相互作用蛋白的特定功能。从这些信息中，我们将更多地了解控制外显子剪接顺序的过程是如何与将基因转录成RNA的过程相协调的。这将帮助我们理解，或许还可以控制细胞如何表达一组独特的基因来生存和生长。

The human genome possesses ~21000 genes; genes encode proteins, but the genes themselves are split, organizing the protein coding regions into discrete blocks called "exons". In each cell only a subset of genes are transcribed into RNA in a process called "transcription". The RNAs are then used to guide the production of proteins of the prescribed sequence. After the genes are transcribed into RNA the exons are stitched together in a process called "splicing". The splicing process can also stitch the exons together in alternative orders which will generate proteins with different sequences and functions. The unique set of proteins within a cell is defined by control processes that regulate transcription and splicing to select which genes and which order of the exons are used. This regulation is a primary means cells modify their protein repertoire to adapt to their environment. Recently, scientists have learned that splicing and transcription are not regulated independently, but are co-regulated by proteins and processes not yet understood. We study two closely related human proteins that may regulate both the order of exons and modulate the level of transcription. These proteins are enzymes, called "kinases", which add a phosphate molecule to sites on other proteins, thus modifying their function. In our experiments we have identified several other proteins that interact with these kinases, thus providing information on how these kinases carry out their functions. In our studies we will characterize the specific functions of both kinases and their interacting proteins. From this information we will learn more about how the process that controls the order of exon splicing is coordinated with the activity of the process that transcribes genes into RNA. This will help us understand, and perhaps control, how cells express a unique set of genes to live and grow.