Molecular and cellular characterisation of an important new human DNA repair disorder

点击翻译按钮获取中文摘要

There are a group of rare inherited genetic disorders that are caused by the mutation of genes that normally act to protect our genes from damage. The chemical that comprises our genetic information, DNA, is susceptible to damage from a wide variety of sources, including environmental exposure or cellular metabolism. Individuals that inherit these DNA damage sensitivity disorders have distinctive combinations of symptoms, resulting from the abnormal behaviour of the mutated genes. These symptoms can include premature ageing, growth defects, neurodegeneration, sunlight or X-ray sensitivity and abnormal skin pigmentation. We recently identified a new syndrome in the Ohio Amish community that is distinct from, but appears related to, known DNA damage sensitivity conditions such as the disorders known as XP (xeroderma pigmentosum), CS (Cockayne's syndrome) or AT (ataxia telangiectasia). The affected individuals have a unique combination of symptoms that led us to hypothesize that a previously unreported mutation must be causing the syndrome. Using state of the art genetic mapping techniques and genome sequencing we have identified the gene and the mutation responsible for causing this disorder.We now need to understand what this particular genetic change does in order to cause the symptoms of the affected individuals. This is important for three reasons. Firstly, if we understand better the problems faced by the cells of affected individuals we should be able to manage their condition more effectively. Secondly, understanding how cells behave when this gene is altered will give us important information about how the unmutated gene normally functions. This is crucial because all our cells are constantly facing DNA damage, and failure to deal with this damage properly can lead to mutations that can result in cancer, ageing and neurodegeneration. A knowledge of the processes that cells normally use to detect, repair or tolerate DNA damage can therefore be hugely valuable in understanding how cancer and neurodegeneration are normally prevented, and what has to go wrong in order for them to occur. Finally, in the clinical setting we use chemicals and treatments that induce DNA damage as chemo- and radio-therapies for many different type of cancer. A better understanding of how our cells tolerate DNA damage, and how specific cells can be made more susceptible to these treatments, can help research aimed at improving therapies and developing novel treatments for malignant disease. Through a longstanding community collaborative program we have unique access to cellular material derived from skin biopsies and blood samples from the affected individuals and unaffected family members. Our proposal is to test these cells in the laboratory to find out how their behaviour differs from normal cells, for example when treated with DNA damaging agents. We will use state-of the-art molecular biology, microscopy and biochemical approaches to uncover why the mutated gene causes these altered cell behaviours. We will throughout the project keep in close communication with the local clinicians to ensure that our findings are used to optimise the treatment of the affected individuals, and we will also make sure that other researchers are informed about our results (via publication, networking and presentation at conferences), so that our research can be translated to generate maximum benefit for human health.