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

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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.