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DNA REPAIR AND CANCER

Objectif

The goal of the Concerted Action is the understanding of the mechanisms of DNA repair and its relationship to cancer, thereby enabling a more rational approach to cancer prevention (identification of carcinogens, eradication of cancer-prone disorders), cancer diagnosis (identification of populations at risk) and cancer therapy.
The relationship between deoxyribonucleic acid (DNA) repair and cancer has been examined in the concerted action using several different approaches
DNA repair diseases (several cancer prone genetic disorders associated with molecular defects in DNA repair continue to be studied in a variety of ways, which reveal the intricacies of the DNA repair processes, as well as helping to understand the mechanism of carcinogenesis);
DNA repair genes and proteins 2 genes, ERCC3 and ERCC6, involved in the excision repair of ultraviolet damage in human cells have been cloned and 2 human genes homologous to the Saccharomyces cerevisiae RAD6 gene have been isolated and chromosomally mapped);
DNA repair proteins (an in vitro system for measuring excision repair of bulky adducts has been developed and characterized);
gene specificity and strand specificity of DNA repair (using yeast as a model system, differential repair of active and inactive genes was observed, and found to be under the control of a number of different genes);
mutagenesis (the conversion of unrepaired DNA damage into permanent mutations represents an important intermediate step in the carcinogenic process and the mechanisms of mutagenesis using DNA sequencing techniques have been investigated);
alkylating agents (using mice as a model system for gene therapy, studies on alkylating agents are of direct relevance for the efficiency of treatment of cancer patients with chemotherapeutic alkylating agents);
inducible effects of DNA damage (Arrand) (the involvement of induced genes in carcinogenesis has been extensively investigated and ultraviolet (UV) inducible phenomena have been studied in bacteria for many years);
detection of DNA damage (techniques of increasing sensitivity have been developedd for measuring different types of DNA damage).
It is now generally accepted that the interaction of chemical carcinogens and/or radiation with cellular DNA is the initiating event in the carcinogenic process. Normal individuals can repair this DNA damage and they only develop tumours at a very low frequency. In contrast, in certain genetic diseases, DNA repair is malfunctional with consequences that are dramatically severe. Patients with xeroderma pigmentosum cannot repair DNA damage caused by ultraviolet light and they develop sunlight-induced skin cancers, including melanoma, in very high numbers. In ataxia-telangiectasia an inability to repair radiation damage is associated with a very high frequency of lymphoid tumours. Moreover, the heterozygous carriers of this disease have an 8-fold increased risk of developing breast cancer. Identification of this population (by means of their DNA-repair defect), which may comprise as mush as 20% of all breast cancer patients, will make a significant contribution towards early diagnosis of breast cancer.

Many therapeutic drugs are in themselves DNA-damaging carcinogens. By understanding their mechanisms of action, it will be possible to design improved drugs whose therapeutic properties remain, while their carcinogenic properties can be reduced.

The Concerted Actio is involved in the European Strategy in the areas of: 1/ Early Detection and Diagnosis: Identification of heterozygous carriers of ataxia-telangiectasia (see above) as a population at risk for breast cancer has important implications for screening for breast cancer;
2/ Improvement of Systemic Treatments: Understanding the mode of action of therapeutic drugs will improve drug design;
3/ Fundamental Research: Our Concerted Action is directly involved in three areas highlighted in the strategy document, namely hereditary cancers, genomic changes in cells and DNA-repair.

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Coordinateur

MRC Cell Mutation Unit
Contribution de l’UE
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Adresse
University of Sussex Falmer
BN1 9RR Brighton
Royaume-Uni

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