Chromosome Breaks and the DNA Damage Response in Transcribed Genes

DNA双链断裂（DSBs）可以通过正常的DNA代谢或暴露于电离辐射（IR）等DNA损伤剂中产生，并可能导致储存遗传信息的染色体断裂。这些病变通常通过两种DSB修复途径之一进行修复，称为非同源末端连接（NHEJ）或同源重组（HR）修复途径。DSB修复很重要，因为不能修复这些病变会导致细胞死亡，而它们的错误修复会引发染色体重排，从而导致癌症。虽然我们对DSB修复的理解已经取得了相当大的进展，但它是如何在转录的背景下发生的，在转录的背景下，基因内的遗传物质被复制成信使RNA以促进蛋白质的产生，尚不清楚。提出的研究目的是了解细胞如何对转录基因内的染色体断裂作出反应，并通过同源重组促进其准确修复。特别是，我们将探讨染色质（DNA被包裹的结构）和转录机制（将DNA复制成信使RNA）在协调这些反应中的作用。拟议的研究将为转录基因中的DSB检测和修复提供机制见解，并进一步研究如何利用这些过程中的缺陷来靶向特定的癌症。

DNA double-strand breaks (DSBs) can arise through normal DNA metabolism or through exposure to DNA damaging agents such as ionizing radiation (IR), and can lead to breaks in our chromosomes which store our genetic information. These lesions are normally repaired by one of two DSB repair pathways termed non-homologous end joining (NHEJ), or homologous recombination (HR) repair pathways. DSB repair is important as failure to repair such lesions can cause cell death, and their misrepair can trigger chromosomal rearrangements, which can lead to cancer. While considerable advances have been made in our understanding of DSB repair, how it occurs in the context of transcription, in which the genetic material within genes is copied into messenger RNA to facilitate protein production, is unclear. The aim of the proposed research is to understand how cells respond to chromosome breaks within transcribed genes and facilitate their accurate repair by homologous recombination. In particular, we will explore the roles of chromatin (structures in which DNA is wrapped up in) and the transcription machinery (which copies DNA into messenger RNA) in coordinating these responses. The proposed research will provide mechanistic insights into DSB detection and repair within transcribed genes, and further, how defects in these processes can be exploited to target particular cancers.