Replication fork stability and fork restart

我们的DNA编码着我们身体的所有特征。它是一个信息库，包含了造就一个人的所有指令。我们体内数以百万计的细胞中，每一个细胞都包含这个文库的两个完整副本，这些文库写在46个DNA分子上。每次我们的一个细胞分裂时，这种DNA都必须被复制。DNA复制是一个非常复杂的过程，几个小时内就能发送几十亿封信息。DNA复制充满了困难，实现这一壮举的复制机制经常受到进展障碍的干扰，这些障碍通常与DNA本身有关。在我们的一个细胞中不能准确地复制DNA的后果是DNA序列的改变。这意味着对库中的信息进行更改。如果许多这样的变化积累起来，这可以重新编程细胞，使其在不应该生长的时候生长。这种不受控制的细胞生长是所有癌症的基础。因此，了解当复制机制在屏障处停止时细胞如何反应是很重要的。利用以单细胞形式生长的有机体（因此相对简单）进行的研究已经发现，当细胞在屏障中受阻时，它们稳定复制机器的许多方法。它还确定了细胞可以重新启动这些被阻止的复制机器的方法。重要的是，虽然以单细胞形式生长的生物体相对简单，但它们处理复制障碍的方式与人类细胞非常相似。因此，在这个工作计划中，我计划使用这些简单生物体中的一种来研究DNA复制机制在遇到复制障碍时稳定的详细机制。我还建议研究当屏障被移除或最终被克服时，这些复制机器是如何重新启动的。重要的是，癌细胞的一个特征是它们比我们体内的其他细胞生长得更快，因此它们更频繁地复制自己的DNA。正因为如此，许多癌症治疗实际上故意引入DNA复制障碍，以选择性地杀死癌细胞。我们希望，通过了解复制机制是如何耐受这些障碍的，我们也许能够找到方法，使癌细胞更有可能被阻碍DNA复制的药物杀死，从而提高癌症治疗的效率。

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.