Avoiding replication trainwrecks - are accessory replicative helicases needed to underpin replication of protein-bound DNA?

对于一个有机体来说，它的细胞分裂和繁殖是必要的。但一个细胞分裂成两个细胞需要复制细胞内的遗传物质。这使得两个子细胞都可以继承基因蓝图的完整副本。如果没有这个蓝图，一个细胞就不能正常运作，最终将死亡。不幸的是，复制细胞的遗传物质是一个非常复杂的过程，部分原因是即使是细菌这样的简单有机体也需要大量的DNA来携带遗传密码。这一过程的复杂性及其至关重要的重要性导致了非常复杂的细胞机器的进化，这种机器可以复制细胞中发现的大量DNA。这些细胞机器可以非常快速、非常准确地复制DNA。然而，我们现在知道，这些机器并不完美，在试图复制遗传密码时经常出现故障。为什么它们会分解？一个主要问题是环境中的某些化学物质以及来自太阳的紫外线等辐射对DNA的破坏。但另一个问题可能是细胞本身造成的。携带遗传密码的DNA实际上并不是孤立地存在于细胞内，而是完全包裹在称为蛋白质的分子中。这些蛋白质对细胞内的几乎每一个过程都是必不可少的，因此在对这些蛋白质的必要性和复制DNA的必要性之间存在着冲突。我们自己和其他人的工作已经证明，这些蛋白质可以阻止DNA复制。我们最近发现，细胞内的某些酶(称为DNA解旋酶)可能通过促进DNA复制机在蛋白质-DNA复合体中的移动来帮助DNA复制。这项研究的目的是确定这些酶是否确实促进DNA的复制，以及这些酶的哪些功能是这种功能所必需的。这将通过分离并在细胞内研究这些酶来实现。这些研究可能有助于我们理解细胞如何在面对许多潜在障碍时复制它们的遗传物质。阻止DNA复制对细胞来说可能是灾难性的。DNA复制失败会阻止细胞分裂，从而产生两个可存活的子细胞。但在DNA复制过程中，堵塞也会导致错误。这些错误可能会导致子代细胞发生突变和随后的功能障碍。在包括人类在内的复杂生物体中，这些功能障碍可能会以遗传疾病和癌症发作的形式出现。我们的工作将有助于理解如何将这些风险降至最低。

For an organism to grow it is necessary that the cells of that organism divide and multiply. But for a cell to divide into two requires that the genetic material within that cell is copied. This allows both daughter cells to inherit a complete copy of the genetic blueprint. Without this blueprint a cell cannot function correctly and will die ultimately. Unfortunately, copying the genetic material of a cell is a very complex process, in part because there is a huge amount of DNA needed to carry the genetic code of even a simple organism such as a bacterium. The complexity of this process, and its critical importance, has led to the evolution of very complex cellular machines that can duplicate the large amounts of DNA found in cells. These cellular machines can copy the DNA very rapidly and very accurately. However, we now know that these machines are not perfect and often break down whilst trying to copy the genetic code. Why do they break down? One major problem is damage to the DNA caused by certain chemicals in the environment and also by radiation such as ultraviolet light from the sun. But another problem might be caused by the cell itself. The DNA carrying the genetic code does not actually exist in isolation within the cell but is completely coated in molecules called proteins. These proteins are essential for nearly every process within the cell and so a conflict exists between the necessity for these proteins and the need to copy the DNA. Our own, and others', work has demonstrated that these proteins can stop the DNA from being copied. We have recently discovered that certain enzymes within a cell (called DNA helicases) might help during duplication of DNA by facilitating the movement of DNA copying machines through protein-DNA complexes. This study aims to establish whether these enzymes do promote copying of DNA and what features of these enzymes are needed for such a function. This will be achieved by studying these enzymes in isolation and also within the context of the cell. These studies may help us to understand how cells duplicate their genetic material in the face of many potential blocks. Blockage of DNA copying is potentially catastrophic for a cell. Failure to copy the DNA prevents a cell from dividing to give two viable daughter cells. But blockage can also lead to errors during this DNA copying process. These errors can cause mutations and consequent malfunctions in daughter cells. In complex organisms, including humans, these malfunctions can take the form of genetic diseases and the onset of cancer. Our work will help understand how these risks might be minimised.