Replication fork stability and fork restart

复制分叉稳定性和分叉重启

• 批准号: G1100074-E01/1
• 负责人: Antony Carr
• 金额: $ 273.47万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100074-E01%2F1
• 关键词: Replication; fork; stability; restart

Our DNA encodes all the characteristics of our bodies. It is a library of information containing all the instructions to make a person. Each of the millions of cells in our bodies contains two complete copies of this library written on 46 DNA molecules. This DNA must be duplicated (replicated) every time one of our cells divides. DNA replication is a very complex process that ?photocopies? several billion letters of information in a few hours. DNA replication is fraught with difficulties and the replication machinery that achieves this feat is frequently disturbed by barriers to progress that are often associated with the DNA itself. The consequence of not accurately replicating the DNA in one of our cells is a change to the DNA sequence. This means a change to the information in the library. If a number of such changes accumulate, this can reprogram a cell to grow when it should not be growing. Such uncontrolled cell growth is the basis of all cancers. It is therefore important to understand how cells respond when the replication machinery stops at a barrier. Work using organisms that grow as single cells, and are thus relatively simple, has identified many ways that cells stabilize replication machines when they are arrested at barriers. It has also identified ways in which cells can restart these arrested replication machines. Importantly, while organisms that grow as single cells are relatively simple, they use very similar ways of dealing with replication barriers as human cells do. In this program of work I therefore plan to use one of these simple organisms to study the detailed mechanism by which the DNA replication machinery is stabilized when it encounters a replication barrier. I also propose to study how these replication machines are restarted when the barrier is removed or finally overcome. Importantly, a feature of cancer cells is that they grow more than other cells in our body and thus they replicate their DNA more often. Because of this, many cancer treatments actually deliberately introduced barriers to DNA replication in order to selectively kill cancer cells. We hope that, by understanding how the replication machinery tolerates such barriers, we may be able to increase the efficiency of cancer treatments by finding ways of making cancer cells even more likely to be killed by drugs that impede DNA replication.

我们的DNA编码身体的所有特征。它是一个包含所有指示的信息库。我们体内数百万个细胞中的每个细胞都包含两个写在46个DNA分子上的文库的完整副本。每当我们的一个细胞分裂时，必须重复（复制）此DNA。 DNA复制是一个非常复杂的过程？复印吗？几个小时内有数十亿封信息。 DNA复制充满了困难和实现此壮举的复制机制经常被与DNA本身相关的障碍所困扰。在我们的一个细胞之一中不准确复制DNA的结果是对DNA序列的变化。这意味着对图书馆中的信息进行更改。如果许多此类变化积累，则可以在不应生长时重新编程细胞生长。这种不受控制的细胞生长是所有癌症的基础。因此，重要的是要了解当复制机械停止在屏障上时细胞的响应。使用作为单个细胞生长的生长并因此相对简单的生长的工作已经确定了许多方法，这些方法在屏障被捕时稳定复制机。它还确定了细胞可以重新启动这些被捕的复制机的方法。重要的是，尽管随着单个细胞而生长的生物相对简单，但它们使用与人类细胞的重复障碍非常相似的方式。因此，在此工作计划中，我计划使用这些简单生物之一来研究DNA复制机制在遇到复制屏障时稳定的详细机制。我还建议研究当屏障被去除或最终克服时如何重新启动这些复制机。重要的是，癌细胞的特征是它们比我们体内的其他细胞生长更多，因此它们更频繁地复制其DNA。因此，许多癌症治疗实际上是故意引入了DNA复制的障碍，以选择性地杀死癌细胞。我们希望，通过了解复制机制如何耐受此类障碍，我们可以通过找到使癌细胞更有可能被阻碍DNA复制的药物杀死的方法来提高癌症治疗的效率。