Role of the BAF180 remodelling complex in transcriptional repression and DNA double strand break repair in mammalian cells.

DNA是一种遗传物质，它对决定我们细胞功能的信息进行编码。DNA是由称为碱基对的构建块组装而成的，碱基对的序列用于制造在细胞内执行工作的酶和蛋白质。因为每个人都来自一个细胞，所以身体中每个细胞的遗传物质应该是相同的。然而，细胞必须经过多次分裂才能形成一个有机体，这就要求我们的DNA被准确地复制。此外，我们的DNA不断受到外部和内部产生的破坏剂的损害。为了保持遗传稳定性，即我们DNA中正确的碱基对序列，这对个体健康和避免癌症至关重要，细胞具有一系列机制，用于修复复制过程中或DNA损伤剂对DNA造成的任何损伤。一种特别危险的损伤是当两条DNA链靠近时发生断裂。这种损伤称为DNA双链断裂（DSB）。如果DSB未修复，细胞将无法复制并死亡，但如果DSB修复不当，其碱基对序列可能会发生改变，这是致癌病因学的一步。DNA被嵌在一层被称为组蛋白的蛋白质外壳中，组蛋白共同形成了一层被称为染色质的DNA保护屏障。然而，染色质在修复过程中可能是难处理的。此外，一系列代谢过程发生在DNA上，这也可以抑制修复过程。编码在DNA中的遗传信息被用来产生蛋白质，即细胞的工作分子。转录是蛋白质从基因序列组装的第一步，转录可以抑制DSB修复过程。因此，细胞进化过程允许染色质被重塑以促进DSB修复，并允许DSB附近的转录被抑制。尽管我们对核心DSB修复过程有很好的了解，但我们对染色质如何被重塑以促进修复的发生以及修复过程如何与转录等过程相结合知之甚少。在初步工作中，我们已经取得了令人兴奋的观察结果，即PBAF复合物是抑制DSB附近转录所必需的，并且PBAF是DSB修复的一个子组分所必需的。本提案的目的是了解更多关于PBAF如何影响DSB的转录以及它如何影响DSB的修复过程。这一点很重要，因为PBAF复合物的一种成分，称为BAF180，在肾癌中经常发生突变。这表明PBAF保护了我们DNA的完整性。因此，了解它如何影响DSB修复和转录过程可以帮助我们了解我们是如何预防癌症的。

DNA is the genetic material which encodes the information that determines the ability of our cells to function. DNA is assembled from building blocks called base pairs, and the sequence of the base pairs is used to create the enzymes and proteins that carry out the work within a cell. Since each individual originates from a single cell, the genetic material of each cell in a body should be identical. However, cells have to go through multiple divisions to generate an organism, which necessitates that our DNA is replicated accurately. Additionally, our DNA is constantly subjected to damage, from both external and internally generated damaging agents. To maintain genetic stability, that is, the correct sequence of base pairs in our DNA, which is critical for the health of the individual and for cancer avoidance, cells have a repertoire of mechanisms that serve to repair any damage to the DNA during replication or from DNA damaging agents. A particularly dangerous lesion is when a break occurs in both DNA strands in close proximity. Such a lesion is called a DNA double strand break (DSB). If a DSB remains unrepaired, the cell will be unable to replicate and can die but, as potentially damaging, if the DSB is misrepaired, the sequence of base pairs can become changed, which is a step in the aetiology of carcinogenesis. DNA is embedded in a coat of proteins called histones, which collectively generate a protective shield to the DNA called chromatin. However, chromatin can be refractory to the repair processes. Additionally, a range of metabolic processes take place on the DNA, which can also inhibit the repair process. The genetic information encoded in the DNA is employed to generate proteins, the worker molecule of a cell. Transcription is the first step by which proteins are assembled from the genetic sequence, and transcription can be inhibitory to the DSB repair process. Thus, the cell has evolved processes that allow the chromatin to be remodelled to facilitate DSB repair and that allow transcription in the vicinity of a DSB to be inhibited. Although, we have a good understanding of the core DSB repair processes, we have very little understanding of how chromatin becomes remodelled to facilitate repair to occur nor how the repair process interface with processes such as transcription. In preliminary work, we have made the exciting observation that the PBAF complex is required for the inhibition of transcription in the vicinity of a DSB and that PBAF is required for a subcomponent of DSB repair. The aim of this proposal is to learn more about how PBAF impacts upon transcription at a DSB and how it influences the DSB repair process. This is important because a component of the PBAF complex, called BAF180, is frequently mutated in cancers of the kidney. This suggests that PBAF protects the integrity of our DNA. Thus, understanding how it impacts upon the process of DSB repair and transcription could help us understand how we are protected against cancer.