Our genetic material, DNA, is the blueprint of our well-being and sometimes the cause of our death (ie. cancer). To maintain its integrity, the genetic material encodes proteins that check its health (DNA repair enzymes) and activity (DNA-methyltransferases). Indeed, abnormalities in either DNA repair or DNA-methylation are frequently observed in cancer cells. Dr. Li’s research focuses on understanding the functions of these proteins. Dysregulation of DNA (cytosine-5) methyltransferase (MCMT) during cancer progression.
Dysregulation of DNA (cytosine-5) methyltransferase (MCMT) during cancer progression.
Genetic analysis of human cancers has revealed that abnormalities in a number of genes are involved in tumor transition. Based on the possible functions of these gene products and the properties of tumor cells, it has been suggested that there exists a genetic hierarchy for tumorigenesis. The more upstream genes can be considered as biological 'Gates' whereas the more downstream genes act as 'Caretakers'. In a model for colon cancer, it has been suggested that the APC gene is a 'Gates' whereas p53 and the mismatch repair proteins are 'Caretakers'. The functional relationships between the 'Gates' and 'Caretakers' genes are unclear, but malfunctions of both types of gene are necessary to cause tumor transformation.
Mutagens, such as chemicals or radiation, damage DNA which if not repaired by DNA repair enzymes will lead to mutations. Mutations are often found in oncogenes or tumor suppressor genes in tumor DNAs. These observations suggest a link between chemicals (and irradiation) and human cancer, i.e. Nucleotide Excision Repair (NER) enzymes in skin cancers (Xeroderma Pigmentosum). In this laboratory, the biological properties of two possible 'Caretakers' gene products that maintain our genomic integrity are being studied. First is the human DNA repair enzyme, 06-methylguanine-DNA methyltransferase (MGMT), which protects humans from environmental alkylating carcinogens (nitrosamines). Second is the human DNA-(Cytosine-5) Methyltransferase (MCMT) which is involved in epigenetic silencing of genes by selective methylation of the cytosine residues in the genomic DNA.
Using purified recombinant proteins, Dr. Li’s group has now characterized the properties of mgmt and mcmt in vitro and raised sensitive monoclonal antibodies to understand their functions in vivo. Recently, laboratory members have made some unexpected findings; MGMT is concentrated at active transcription sites and MCMT is a key component of cell-cycle regulation. Ongoing and future work may enable the development of useful strategies to monitor human exposure to chemical carcinogens and to establish a sensitive biomarker for tumor progression.