The long-term goal of our lab research is to understand the molecular mechanisms involved in maintaining genome stability. To this end, we investigate what and how trans-acting factors are involved in maintaining genome stability. The major focuses of our ongoing research activities are:
(I) To investigate mutator phenotypes induced by aberrant chromosome replication.
Cancer is a genetic disease, arising from an accumulation of mutations that promote clonal selection of cells with increasing mutations i.e. mutator phenotype. The accumulation in cancer cells genome of hundreds of thousands of mutations such as insertion and deletions of sequences and alterations of repeat sequences is the diagnostic feature of cancer. We investigate what and how mutations in enzymes/proteins essential for chromosome replication can cause an aberrant replication resulting in genomic instability.
We have used Schizosaccharomyces pombe (S. pombe) and Saccharomyces cerevisiae (S. cerevisiae) as the model organisms to identify replication mutants that have an elevated mutation frequency in deletion or duplication of genomic sequences flanked by short direct repeats as well as alterations of dinucleotide repeats. Identical or similar mutations are being introduced into mammalian homolog replication enzymes/proteins to investigate whether they could generate a mutator phenotype in animal cell lines. We plan in the near future to express these replication mutants with a tissue specific promoter in a specific organ of mice to test their carcinogenic effect during the tissue development.
(II) To investigate the genetic and biochemical elements that maintain the DNA replication checkpoint.
There is a category of genes encoding components of the cell cycle checkpoints. Cell cycle checkpoints are positions of control to ensure the order of events in the cell cycle and to integrate DNA repair with cell cycle progression.
Our laboratory has used fission yeast as the model organism to investigate what is required for cells to activate intra-S phase checkpoint and how cells prevent premature mitotic entry when DNA replication is unfinished or improperly initiated. We have used various mutants of chromosome replication genes to investigate what cell cycle checkpoint gene products are activated and how they monitor S phase delay and S phase arrest. We first use genetic approaches to identify genes that sense and transduce the signals of replication delay or block. We then use biochemical methods to investigate these S-phase checkpoint gene products. Our future goal is to introduce mutations of the S phase checkpoint genes into mammalian homolog genes to directly test the carcinogenic effect in mammalian cells.
Last updated: November 12, 1999
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