Molecular Mechanism for Maintainance of Genetic Information

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The aim of this research is to analyze a molecular mechanism for maintainance of genetic information in higher eukaryotes including human and to analyze its role in embryogenesis, development, aging and carcinogenesis. Major achievements in this research are as follows. Group I : We cloned genes of photolyases for pyrimidine dimer and (6-4) photoproduct from prokaryotes, kangaroo rat, drosophila melanogaster, and goldfish. Human homologue of these photolyase genes has been cloned as well and functional analysis of the human homologue is in progress. We cloned the genes responsible for xeroderma pigmentosum groups A,C,and G,and analyzed their roles in the early steps of nucleotide excision repair and molecular basis of their deficiencies. Higher order structures of the three DNA repair proteins have been revealed by X-ray crystallography. Group II : We elucidated the control mechanisms of gene expression for PCNA and DNA polymerase beta. We cloned a mismatch repair gene MSH3 and found t … More hat the expression of the MSH3 gene was reduced in the leukemic cells which were RER positive. We found that the enzyme activity to repair 8-OH-Gua damage caused by the active oxygen was increased by the treatment with oxygen stress, smoking and aging. Group III : By the method of gene targeting in mouse ES cells, we established XPA-deficient or XPG-deficient mice, and O6-methylguanine-DNA-methyltransferase-deficient or 8-oxo-dGTPase-deficient mice. We also established RAD51-deficient mice which were lethal at the embryonal stage. The XPA-deficient mice were highly susceptible to UVB-induced skin carcinogenesis. Based on these results we concluded that we have accomplished the initial research projects such as molecular cloning of the important DNA repair genes, structural analysis of DNA repair proteins by X-ray crystallography and establishment of DNA repair gene-deficient mice by gene targeting. These achievements provide a basis for the breakthrough to unveiling the molecular mechanism for maintainance of genetic information. Less