Ubiquitylation within and beyond the DNA damage response

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As we age our cells become increasingly sensitive to accumulating damage in their genetic makeup, which is formed by a complex molecule called DNA. DNA damage happens frequently, for instance through radiation, sunlight, chemicals in tobacco smoke, and even from the oxygen in the air we breathe. A rise in DNA damage is linked to some of the most severe and common problems that prevent us from healthy ageing. This includes cancer and diseases of the brain, such as loss of mental abilities. In fact, certain permanent DNA changes that affect the ability of cells to repair DNA damage, can lead to an early onset of these diseases and to premature ageing itself. With the global population ageing, the burden of age-related disorders will steadily increase. It is therefore of urgent importance that we understand better how cells prevent DNA damage. This could lead to ways to prevent these disorders and thus, contribute to healthy ageing across the lifespan.To prevent permanent DNA damage, cells have found many different ways to repair the damaged DNA. Hundreds of proteins -the workhorses of the cell- need to quickly change their behaviour in highly organised ways, an amazing feat that is far from being properly understood. While cells can make use of an elaborate toolkit for this, the following way is especially fascinating: a little protein, known as ubiquitin, is attached to other proteins. Ubiquitin can be attached in different ways, as a single ubiquitin or as poly-ubiquitin chains made up of many ubiquitins glued together in different ways. The process of ubiquitin attachment is called ubiquitylation. The ubiquitylated proteins are recognised by other proteins, which trigger the final change in the behaviour of the ubiquitylated protein. Ubiquitylation relies on several enzyme groups, including ones known as E2s. I have recently found that several E2s play fundamental roles in repairing DNA damage. Through using novel techniques that I have been key in developing, one of the major aims of the proposal is to better understand how precisely different E2s accomplish DNA repair. This could highlight their potential as drug targets, meaning that they could be changed by a medicine to give a desirable effect. Such an effect could for instance be towards treating age-related diseases such as cancer. Moreover, my recent findings suggest that many more proteins recognise and translate ubiquitylated proteins than is currently expected. Another key aim of the proposal is therefore to analyse these ubiquitin binding proteins. By doing so the proposed work will transform our understanding of how different ubiquitylations change the behaviour of proteins in defined organised ways. These discoveries could be attractive to the commercial sector, as they have potential to be developed into general ubiquitin research tools. Since ubiquitylation is involved in almost every aspect of cell biology, the proposed work is likely to have a wide impact regarding this.Taken together, the proposed research will increase our fundamental knowledge of how ubiquitylation regulates the DNA damage response and associated processes. This is crucial to maintaining DNA integrity. Given the significance of the DNA damage response for preventing various age-related disorders, the work may pave the way for the development of new medicines contributing to healthy ageing throughout life.