Defects in replicative DNA polymerases linked to cancer predisposition and tumour development

我们的遗传物质不断受到破坏。这种损害大部分不是来自外部来源，如致癌物或辐射，而是来自DNA必须执行的内在生物过程，以使我们的细胞发挥作用。DNA的一个关键的生物学功能包括它的复制，因此在细胞分裂过程中产生的两个子细胞中的每一个都得到了所有遗传信息的完整而准确的副本。即使在正常细胞中，这种复制过程也不是100%完美，由此产生的错误可能导致改变细胞功能的突变，可能导致细胞死亡或其他可能导致癌症的变化。最近的发现表明，一些癌症与复制DNA的聚合酶的缺陷有关。DNA聚合酶通常是高度准确的，但这些聚合酶的缺陷会增加基因组复制时的错误率，这可能会加速细胞增殖率高的组织中某些类型癌症的发展。在这项资助中，我们将详细研究这些有缺陷的聚合酶，以了解在人类细胞中发现的哪些变化可能是致病的。我们将研究聚合酶如何发生故障，染色体复制过程的后果以及由此导致的复制错误的类型。了解癌症相关DNA聚合酶的特性将有助于解释这些缺陷是如何导致肿瘤形成的。也有可能开发出针对表达这些变异聚合酶的肿瘤细胞复制的药物。

Our genetic material is constantly subjected to damage. Much of this damage comes not from external sources such as carcinogens or radiation, but from the intrinsic biological processes that DNA has to perform to allow our cells to function. One key biological function of DNA involves its replication, so that each of the two daughter cells produced during cell division receives a complete and accurate copy of all the genetic information. Even in normal cells, this copying process is not 100% perfect, and the resulting errors can lead to mutations that alter cell function, potentially leading to cell death or other changes that can lead to cancer. Recent findings have shown that some cancers are associated with defects in the polymerase enzymes that copy DNA. DNA polymerases are normally highly accurate, but defects in these polymerases can increase the error rate when the genome is copied, and this can accelerate the development of some types of cancer in tissues where there is a high rate of cell multiplication. In this grant we will study these defective polymerases in detail, to understand which changes found in human cells are likely to be pathogenic. We will study how the polymerase malfunctions, the consequences for the process of chromosome replication and the types of copying mistakes which result. Understanding the properties of the cancer-associated DNA polymerase should help to explain how these defects lead to tumour formation. It is also possible that drugs might be developed that target the replication of tumour cells that express these variant polymerases.