Chromosome Breaks and the DNA Damage Response in Transcribed Genes

DNA双链断裂(DSB)可通过正常的DNA代谢或暴露于DNA损伤剂(如电离辐射(IR))而发生，并可导致存储遗传信息的染色体断裂。这些损伤通常由两条DSB修复途径之一修复，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，因为如果不能修复这种损伤会导致细胞死亡，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很大的进展，但它是如何在转录的背景下发生的，即基因中的遗传物质被复制到信使RNA中以促进蛋白质的生产，目前还不清楚。这项拟议研究的目的是了解细胞如何对转录基因中的染色体断裂做出反应，并通过同源重组促进它们的准确修复。特别是，我们将探索染色质(包裹DNA的结构)和转录机制(将DNA复制到信使RNA中)在协调这些反应中的作用。这项拟议的研究将提供对转录基因中DSB检测和修复的机械性见解，以及如何利用这些过程中的缺陷来针对特定的癌症。

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.