Final Activity Report Summary - CLUSTOXDNA (Selective formation and biochemistry of oxidative clustered DNA damage)
A major problem in the coming years is that the average population age and the health costs associated with typical diseases of the elderly are dramatically increasing. The number of arthritis patients, as well as of those that spontaneously develop cancer or are hampered by strokes is also rapidly increasing. All these diseases are directly related, at least partially, to oxidative damage to the genetic material, i.e. the deoxyribonucleic acid (DNA) in cells. The DNA is an important target for very reactive free radicals to cause clusters of damage sites very close to one another. These clusters are very difficult to correct as the repair proteins do not easily recognise the damage. If the damage is not removed by proteins to restore the correct genetic code, potentially harmful effects are caused by free radicals. As a consequence, significant health effects, such as cancer or several late effects may arise. The biological consequences of clustered DNA damage are thought to play a major role in cancer and degenerative diseases of the aging population. It is therefore of paramount importance to understand the biological consequences of oxidative DNA lesions and identify avenues for the development of preventative interventions.
the project partners were the following:
1. Medical Research Council, RAGSU, Harwell, United Kingdom
2. Commissariat à l Energie Atomique, Grenoble, France
3. Ludwig-Maximilians Universität München, Germany
4. Consiglio Nazionale delle Ricerche, Bologna, Italy
5. Universidad Politecnica de Valencia, Spain
6. National Kapodistrian University of Athens, Greece
7. Institute of Solid State Physics, Bulgarian Academy of Sciences, Sofia, Bulgaria
8. Johannes Gutenberg-Universität Mainz, Germany.
The primary research objectives of CLUSTOXDNA were to understand how oxidatively induced clustered DNA damaged and closely spaced lesions interfere with the cells ability to maintain the stability of the genetic code. This objective was addressed at the cellular level using chemical or biochemical technology and utilising a variety of multi-disciplinary approaches, and focussed on understanding in detail the biological consequences of clusters of DNA damage sites in cells.
Novel DNA lesions which were not commercially available were synthesised and incorporated into short lengths of specific DNA so as to understand the ways in which reactive free radicals caused the DNA to be damaged. Novel information was obtained regarding how the structure was distorted by the damage site in DNA so that the molecules that repaired the lesion had difficulty in recognising the damage, similar to a key no longer fitting the lock. Importantly, the clustering of DNA damage sites was uniquely detected in mammalian cells. Biochemical studies indicated that these clusters of DNA damage sites were difficult to repair and, as a consequence, they caused long-lived genetic changes. The novel DNA lesions that were synthesised led to important findings emphasising the biological significance of oxidative and radiation-induced genetic changes in cells and their significance in the development of diseases relating to ageing. The structural and biochemical information on genetic damage would inform the community of potential target sites for intervention of relevance to minimise free radical induced disease.
The multi-disciplinary collaboration offered added European competitiveness through bringing together different expertise and dissemination through publications, the project website and public presentations. The network provided unique training opportunities and benefits to young researchers which were interested in gaining training in different aspects of the field. A pool of young researchers was trained on the importance of inter-disciplinary research and the added value of complementary collaborations. The European Union funding facilitated the synergism between European experts with different expertise who were brought together under a common umbrella.
the project partners were the following:
1. Medical Research Council, RAGSU, Harwell, United Kingdom
2. Commissariat à l Energie Atomique, Grenoble, France
3. Ludwig-Maximilians Universität München, Germany
4. Consiglio Nazionale delle Ricerche, Bologna, Italy
5. Universidad Politecnica de Valencia, Spain
6. National Kapodistrian University of Athens, Greece
7. Institute of Solid State Physics, Bulgarian Academy of Sciences, Sofia, Bulgaria
8. Johannes Gutenberg-Universität Mainz, Germany.
The primary research objectives of CLUSTOXDNA were to understand how oxidatively induced clustered DNA damaged and closely spaced lesions interfere with the cells ability to maintain the stability of the genetic code. This objective was addressed at the cellular level using chemical or biochemical technology and utilising a variety of multi-disciplinary approaches, and focussed on understanding in detail the biological consequences of clusters of DNA damage sites in cells.
Novel DNA lesions which were not commercially available were synthesised and incorporated into short lengths of specific DNA so as to understand the ways in which reactive free radicals caused the DNA to be damaged. Novel information was obtained regarding how the structure was distorted by the damage site in DNA so that the molecules that repaired the lesion had difficulty in recognising the damage, similar to a key no longer fitting the lock. Importantly, the clustering of DNA damage sites was uniquely detected in mammalian cells. Biochemical studies indicated that these clusters of DNA damage sites were difficult to repair and, as a consequence, they caused long-lived genetic changes. The novel DNA lesions that were synthesised led to important findings emphasising the biological significance of oxidative and radiation-induced genetic changes in cells and their significance in the development of diseases relating to ageing. The structural and biochemical information on genetic damage would inform the community of potential target sites for intervention of relevance to minimise free radical induced disease.
The multi-disciplinary collaboration offered added European competitiveness through bringing together different expertise and dissemination through publications, the project website and public presentations. The network provided unique training opportunities and benefits to young researchers which were interested in gaining training in different aspects of the field. A pool of young researchers was trained on the importance of inter-disciplinary research and the added value of complementary collaborations. The European Union funding facilitated the synergism between European experts with different expertise who were brought together under a common umbrella.