Termination of DNA replication - a novel threat to genomic stability and cell cycle control

癌症正迅速成为人类最常见的死亡原因之一，超过三分之一的人将在其一生中患上癌症。癌症的一个特征是细胞不受控制的生长，这通常是通过控制机制网络来阻止的，这些机制限制了正常细胞可以进行的分裂次数。受损或达到一定年龄的细胞被阻止进一步分裂，以消除它们癌变的可能性。然而，这种持续清除老的和受损的细胞是有代价的。虽然它避免了癌细胞的形成，但它也越来越阻碍组织的再生，这被认为是导致个体衰老过程的一个主要因素。因此，肿瘤发生和衰老是相互对立但又紧密相连的力量。到目前为止，我对癌症遗传学和衰老的兴趣是我学习分子生物学和大部分研究的主要动机之一。最初，癌症的医学方面是我的主要兴趣。我在人类遗传学实验室呆了几个月，直接研究癌组织。然而，这份工作虽然有趣，却让我很不满意。人们对人类细胞中癌症发展的细节知之甚少，我所做的研究感觉就像是在黑暗中打针。不久之后，我在一个实验室里上了一门课程，对烘焙酵母的基因组稳定性很感兴趣。在这里，我经历了对酵母中DNA代谢的分子细节的理解比人类细胞要先进得多。我能够做一些简单的实验，让我明白为什么基因信息变得不稳定。在人类中，缺乏基因组稳定性是导致正常细胞转化为癌细胞的关键阶段之一，因为它破坏了维持基因组完整性的质量控制系统的复杂网络，并确保细胞只在安全的情况下分裂。受癌症生物学这一关键特征的激励，我继续研究当时新发现的一种名为Mph1的酵母蛋白是如何帮助维持遗传信息的。这些研究为我的文凭和随后的博士培训奠定了基础。在人类身上也发现了类似的蛋白质。它之所以被称为FancM，是因为缺乏它会导致范可尼贫血，这是一种与癌症风险高得多相关的遗传性疾病。看到酵母蛋白的研究如何能引起人类遗传学家的兴趣是令人兴奋的。完成博士学位后，我决定研究一种叫做RecG的蛋白质，这是一种DNA加工酶，几乎在所有种类的细菌中都有发现。人们认为RecG、Mph1和FancM可能在DNA代谢中具有相似的功能。然而，我的研究表明，RecG有一个重要的和以前未知的功能。它限制了基因组不稳定的一个主要原因，它与有序完成染色体复制所必需的事件有关，染色体复制是所有生物体的基本要求。这种基因组不稳定性的触发是出乎意料的，我对解剖分子细节的前景感到兴奋。最终，我的目标是了解它是如何导致癌症和衰老的。然而，我的初步研究将继续探索更容易处理的细菌模型，以便在进一步研究更复杂的系统之前建立一些基本的认识。因此，我的研究也将阐明基因组不稳定性的各个方面，使细菌病原体能够克服宿主的防御并获得对抗生素的耐药性。

Cancer is rapidly becoming one of the most common causes of death in human populations, and more than one in three individuals will suffer from it within their lifetime. A hallmark of cancer is the uncontrolled growth of cells, which is normally prevented by a network of control mechanisms that restricts the number of divisions normal cells can do. Cells that are damaged or have reached a certain age are prevented from any further divisions to remove the potential for them becoming cancerous. However, this continuous removal of old and damaged cells comes at a cost. While it avoids the formation of cancerous cells, it also increasingly impedes the regeneration of tissues, which is thought to be a major factor contributing to the ageing process of an individual. Thus, oncogenesis and ageing are opposite but tightly linked forces. My interest in cancer genetics and ageing was one of the key motivations for studying molecular biology and for most of my research up to now. Initially, the medical aspects of cancer were my main interest. I spent several months in a human genetics laboratory where I worked directly with cancerous tissue. However, this work, although interesting, left me rather unsatisfied. Little was known about the details of cancer development in human cells and the studies I was doing felt rather like shots in the dark. Shortly afterwards I did a course in a lab that was interested in genomic stability in baker's yeast. Here I experienced that the understanding of the molecular details of DNA metabolism in yeast was far advanced in comparison to human cells. I was able to do simple experiments that allowed me to understand why the genetic information became unstable. In humans this lack of genomic stability is one of the key stages that results in transformation of a normal cell into a cancer cell, as it corrodes the complex network of quality control systems that maintains genomic integrity and ensures that cells only divide once it is safe to do so. Motivated by this key feature of the biology of cancer, I went on to investigate how a specific yeast protein called Mph1, which was newly discovered at the time, helps to maintain the genetic information. These studies formed the basis of my Diploma and subsequent PhD training. A similar protein has been identified in humans. It is called FancM since its absence causes Fanconi anemia, a genetic disease associated with a much-elevated risk of cancer. It was exciting to see how investigations of a yeast protein can be of interest for human geneticists.After completing my PhD I decided to study a protein called RecG, a DNA processing enzyme found in almost all species of bacteria. It was thought that RecG, Mph1 and FancM might all have a similar function in DNA metabolism. However, my studies revealed that RecG has an important and previously unknown function. It limits a major cause of genomic instability, one associated with events necessary for the orderly completion of chromosome replication, a fundamental requirement in all organisms. This trigger of genomic instability was unexpected and I am excited by the prospect of dissecting the molecular details. Ultimately, I aim to understand how it might contribute to the development of cancer and ageing. However, my initial studies will continue to exploit more tractable bacterial models so as to build some basic understanding before progressing to the more complex systems operating in higher organisms. As such my studies will also shed light on aspects of genomic instability that enable bacterial pathogens to overcome host defences and to acquire resistance to antibiotics.