Epigenetic gene silencing of tumor suppressor genes in cancer has emerged as a major mechanism that rivals mutation. Methylation of CpG islands, a key event in epigenetic gene silencing, is due to the activity of the cytosine DNA methyltransferases (DNMTs). The role of the DNMTs in epigenetic gene silencing of tumor suppressor genes and lung cancer progression will be determined through three specific aims. The first aim is to identify the effect that exposure of human telomerase (hTERT) immortalized bronchial epithelial cells to tobacco carcinogens has on expression of the cytosine DNA methyltransferases DNMT1, DNMTSa, DNMTSb, gene-specific promoter hypermethylation, and cellular transformation. The next aim is to determine the effect that exogenously overexpressing either cfe novo cytosine DNA methyltransferase DNMTSa or DNMTSb, alone or in conjunction with carcinogen exposure, has on cellular transformation and gene-specific promoter hypermethylation. Then, the effect that down regulating DNMT1, DNMTSa, or DNMTSb using RNA interference has on the ability of carcinogen exposure to induce gene-specific promoter hypermethylation and cellular transformation will be elucidated.