Studies on the function of Werner syndrome gene product and analyses of the mechanism to induce aging related symptoms

点击翻译按钮获取中文摘要

The aim of this study is to clarify the mechanism to cause predisposition of cancer due to genome instability and many aging related symptoms including type II diabetes mellitus in Werner syndrome patients by investigating the functions of WRN in DNA replication and repair. In this study, we used yeast model system to know the functional relationship between WRN, WRNIP1 and DNA polymerase δ (Polδ), and various gene disrupted chicken DT40 cells to analyze the pathway in which WRN functions. In addition, we performed biochemical analyses using purified enzymes and proteins. We isolated many mutants having mutations in the subunit of Polδ, pol31 and got evidence indicating functional relationship between WRN, WRNIP1 and pol31. In addition, by using many DT40 mutants it was suggested that WRN functions with RAD52 and in the pathway in which RAD18 is involved when cells are caused specific DNA lesions. Furthermore, it was suggested that WRNIP1 functions upstream of RAD18 and directly interacts with RAD18. Finally, we established the base to know the function of WRN under oxidative stress by constructing SOD1 or SOD2 gene defective mutants using DT40 cells.