DNA repair genes represent a class of tumor suppressor genest hat have proven increasingly important in preventing cancer development in humans. This is not unexpected as DNA repair has been demonstrated to have a crucial role in maintaining genome stabil ity. DNA damage induced by cellular exposure |to environmental chemical and physical agents as well as those induced by endogenous metabolites, e.g. oxygen radical species, are rapidly and faithfully removed by efficient repair mechanisms. At present, mor e than 150 h\genes have been recognized in human cells, constituting at least six different pathways. Normally, it is only a small fraction of the damages formed that will remain to induce mutations and other detrimental effects on living cells. However, defects in DNA repair will greatly sensitize cells to exposure to mutagenic and carcinogenic agents and the rate of mutations increases radically by inactivation of repair genes. The classical example is natural mutations occurring in xeroderma pigmentosu m genes in man that imposes extreme sensitivity to sunlight and will induce skin cancer in all affected individuals within the age 10-20 years. The overall aim of the proposed project is to improve our understanding of the relationship between deficiencie s, mutations and polymorphisms in DNA repair genes and the development of cancer. The work involves mechanistic and functional analysis of different DNA repair pathways in cancer as well as in normal cells to determine more precisely their role in prevent ing genome instability and cancer susceptibility. It also includes searches for new polymorphisms and mutations in repair genes associated with cancer development. Special emphasis will be put on the role of base excision repair since this pathway is esse ntial for removing endogenous as well as exogenous DNA damage and will also protect from detrimental effects of chronic inflammation often associated with common types of cancer.