'How is PtdIns(4,5)P2, a membrane lipid messenger, localised and regulated in splicing speckles, a membrane less compartment within the nucleus?

DNA是人类生命的密码，它组成了用于生产蛋白质的基因。蛋白质是细胞用来执行特定功能的分子主力。我们体内的细胞不断受到压力的攻击，这会导致它们的破坏和死亡。例如，许多不同的环境暴露会导致我们的DNA受损。这可能包括阳光或空气中的有害化学物质。DNA是我们细胞的基石，如果它受损，细胞就不能正常运作，这要么会导致细胞死亡，要么经常会导致癌症等疾病的发展。DNA被包含在细胞的一个特殊的隔间，称为细胞核。为了对这些破坏我们DNA的应激源做出反应，细胞必须意识到或感觉到损害，然后必须启动适当的反应。细胞中有一种高度复杂的机制，可以感知受损的DNA，当它这样做时，会发出适当的信号，通知细胞改变自己的行为并对此做出反应。其中一个信号是由一系列脂类或脂肪分子组成的，统称为磷脂酰肌醇或PPIN。由于它们的化学成分，这些脂肪分子喜欢与其他脂肪分子粘在一起，通常情况下，这些脂肪分子形成一层膜，有点像肥皂泡。事实上，细胞膜是构成细胞外部的物质。然而，令人惊讶的是，在细胞核中，这些PPIns分子位于一个特殊的位置，称为剪接斑点，已知这种斑点没有任何膜。PPIN是如何到达斑点的，它们是如何保存在那里的，这是一个我们现在开始了解的谜团。在细胞核中，这些斑点参与了一种相当特殊的功能，称为剪接，帮助细胞利用DNA制造蛋白质。DNA说明书有一个特殊的结构。它包含被称为编码蛋白质的基因的区域。这些基因由较小的DNA片段组成；其中一些编码部分蛋白质，称为外显子，而外显子之间的其他部分包含无意义的编码，称为内含子。制造蛋白质的指令依赖于拼接DNA的编码外显子，同时去除内含子。为了在不丢失细胞DNA复制的情况下做到这一点，它首先被复制到一种名为RNA的类似分子中，该分子包含外显子和内含子。然后去除无意义的内含子，这个过程被称为剪接。一旦内含子被移除，RNA就可以用来制造蛋白质，帮助细胞对应激源做出反应。我们认为，这些PPIN是整个进程的关键部分。作为对压力源的反应，斑点处的这些PPIN的数量似乎增加了。值得注意的是，这些PPIN具有吸引特殊蛋白质并与之对话的能力，并改变它们在细胞中的位置以及它们执行功能的方式。事实证明，事实上，它们与许多参与剪接的蛋白质结合并交谈。这项研究的一部分将准确地找出DNA损伤如何改变斑点上PPIN的数量，以及哪些剪接蛋白对PPIN的增加做出反应。这遗漏了关于PPIN是如何到达并停留在斑点中的谜团。以一种美丽的协调方式，我们发现参与剪接的一种蛋白质，称为SRSF2，能够与PPIN结合，这对于将PPIN带到斑点并将它们保持在那里至关重要。SRSF2如何做到这一点将成为本研究的主要部分。剪接工作的好坏对生命本身以及在人类生命过程中剪接能力的变化是至关重要的，此外，SRSF2在血癌中经常发生突变。PPIN是由一种称为酶的蛋白质家族制造和移除的，我们希望制造出类似药物的分子来抑制它们。这些可以被用来专门控制细胞核中的PPIN水平；然后可以用来治疗几种疾病，比如癌症，或许还可以帮助衰老。

DNA is the code for human life that makes up genes that are used to produce proteins. Proteins are the molecular workhorses that are used by cells to carry out specific functions. Cells in our bodies are constantly under attack from stressors which lead to their damage and demise. For example, many different environmental exposures lead to damage of our DNA. This can include sunlight or harmful chemicals in the air. DNA is the building blocks of our cells, and if it becomes damaged the cell cannot function properly and this can either lead to the cell dying, or often can lead to the development of diseases such as cancer. DNA is contained in a specialised compartment of the cells called the nucleus. To respond to these stressors that damage our DNA, cells have to be made aware of, or sense, the damage and then have to initiate an appropriate response. There is a highly sophisticated machinery in cells that can sense damaged DNA, and when it does so sends an appropriate signal to inform the cell to change its behaviour and respond to it. One of these signals is made up of a family of lipids or fat molecules collectively called phosphoinositides or PPIns for short. Because of their chemical composition these fat molecules like to stay together with other fat molecules which normally forms a membrane, rather like a soap bubble. In fact, the membrane is what forms the outside of a cell. However, in the nucleus surprisingly, these PPIns molecules sit in a specialised place called a splicing speckle which are known not to have any membranes. How PPIns arrive at the speckles and how they are kept there is a mystery which we are now beginning to understand. In the nucleus these speckles are involved in a rather special function, called splicing, that helps the cell to use the DNA to produce proteins. The DNA instruction manual has a peculiar structure. It contains regions called genes which code for proteins. These genes are made up of smaller blocks of DNA; some of which code for part of the protein and are called exons, and other parts between the exons that contain nonsense code called introns. The instructions to make a protein rely on piecing together the coding exons of the DNA while removing the introns. To do this without losing the cells copy of DNA, it is first copied into a similar molecule called RNA, which contains the exons and introns. The nonsense introns are then removed and this process is called splicing. Once the introns have been removed, the RNA can be used to make proteins to help the cell to respond to the stressors. We think that these PPIns are a key part of the whole process. In response to stressors it seems that the amount of these PPIns at the speckle goes up. Remarkably these PPIns have an ability to be able to attract and talk to special proteins and change where they are in the cell and how well they carry out their functions. It turns out that in fact, they bind and talk to many of the proteins that are involved in splicing. Part of this study will work out exactly how DNA damage changes the amount of PPIns at the speckle, and which splicing proteins respond to the increase in PPIns. What this leaves out is the mystery about how the PPIns arrive and stay in the speckle. In a beautifully coordinated manner, we have found that one of the proteins that is involved in splicing, called SRSF2, is able to bind to PPIns and is critical for bringing the PPIns to the speckle and holding them there. How SRSF2 does this will form a major part of this study.How well splicing works is fundamental to life itself and during human life splicing ability changes, Moreover, SRSF2 is often mutated in blood cancers. PPIns are made and removed by a family of proteins called enzymes and we hope to make drug like molecules that inhibit them. These could be used to specifically control the levels of PPIns in the nucleus; which could then be used to treat several diseases such as cancer and perhaps help during ageing.