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

“PtdIns(4,5)P2（一种膜脂信使）如何在剪接斑点（细胞核内的无膜区室）中定位和调节？

• 批准号: BB/Y001648/1
• 负责人: Nullin Divecha
• 金额: $ 110.7万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY001648%2F1
• 关键词: How; PtdIns; P2; membrane; lipid

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.

DNA 是人类生命的密码，它构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源的攻击，导致细胞受损和死亡。例如，许多不同的环境暴露都会导致我们的 DNA 受损。这可能包括阳光或空气中的有害化学物质。 DNA 是我们细胞的组成部分，如果它受损，细胞就无法正常运作，这可能导致细胞死亡，或者经常导致癌症等疾病的发展。 DNA 包含在称为细​​胞核的细胞特殊区室中。为了应对这些损害我们 DNA 的压力源，细胞必须意识到或感知到这种损害，然后启动适当的反应。细胞中有一个高度复杂的机制，可以感知受损的 DNA，当它这样做时，会发送适当的信号，通知细胞改变其行为并对其做出反应。其中一个信号由一系列脂质或脂肪分子组成，统称为磷酸肌醇，简称为 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呆在一起，这些分子通常形成一层膜，就像肥皂泡一样。事实上，膜是细胞外部的组成部分。然而，令人惊讶的是，在细胞核中，这些 PPIns 分子位于一个称为剪接斑点的特殊位置，已知该位置没有任何膜。 PPIns 如何到达斑点以及它们如何保持在那里是一个我们现在开始了解的谜团。在细胞核中，这些斑点参与一种相当特殊的功能，称为剪接，帮助细胞利用 DNA 产生蛋白质。 DNA说明书有一个特殊的结构。它包含编码蛋白质的称为基因的区域。这些基因由较小的 DNA 块组成；其中一些编码蛋白质的一部分，称为外显子，而外显子之间包含无义代码的其他部分称为内含子。制造蛋白质的指令依赖于将 DNA 的编码外显子拼凑在一起，同时去除内含子。为了在不丢失细胞 DNA 拷贝的情况下做到这一点，它首先被复制到一种称为 RNA 的类似分子中，其中包含外显子和内含子。然后去除无义内含子，这个过程称为剪接。一旦内含子被去除，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 是整个过程的关键部分。为了应对压力源，斑点处这些 PPIn 的数量似乎会增加。值得注意的是，这些 PPIn 能够吸引特殊蛋白质并与之对话，并改变它们在细胞中的位置以及它们执行功能的能力。事实证明，事实上，它们与许多参与剪接的蛋白质结合并与之对话。这项研究的一部分将弄清楚 DNA 损伤如何改变斑点处 PPIn 的数量，以及哪些剪接蛋白对 PPIn 的增加做出反应。这就遗漏了 PPIn 如何到达并停留在散斑中的谜团。我们发现，以一种完美协调的方式参与剪接的蛋白质 SRSF2 能够与 PPIn 结合，并且对于将 PPIn 带到斑点并将其固定在那里至关重要。 SRSF2如何做到这一点将构成本研究的主要部分。剪接的效果如何对于生命本身以及人类生命中剪接能力变化至关重要，此外，SRSF2在血癌中经常发生突变。 PPIns 是由一种叫做酶的蛋白质家族产生和去除的，我们希望制造出类似药物的分子来抑制它们。这些可用于专门控制细胞核中 PPIn 的水平；然后它可以用来治疗癌症等多种疾病，或许还有助于延缓衰老。