Molecular mechanism to cause high incidence of cancer in Bloom syndrcme

点击翻译按钮获取中文摘要

Bloom's syndrome is autosomal disorder characterized by predisposition to wide variety of cancers. In this study, I intended to clarify the function of the Bloom syndrome gene product (BLM) at the molecular level, using budding yeasts that have a BLM homologue, SGS1 as well as higher eukaryotic cells. Genetical analyses using yeasts indicated that Sgs1 functions to suppress homologous recombination under normal condition. However, Sgs1 was required to induce homologous recombination when cells were injured with DNA damaging agents. It has been revealed that the interaction of Sgs1 with DNA topoisomerase III (Top3) is essential for Sgs1 to fulfill its function and that Sgs1 functions in the Rad52 recombination pathway involving Rad51 but not Mre11.To elucidate the function of Top3 and functional relationship between BLM and Top3 in higher eukaryotic cells, we constructed cells with various genetic backgrounds whose Top3a expression is controllable. Depletion of Top3a from the cells caused accumulation of cells in G2 phase, enlargement of nuclei, chromosome gaps and breaks that occurred at the same position of sister chromatids, and inhibition of transition from metaphase to anaphase and that these events were suppressed by disruption of BLM gene, indicating a functional interaction between BLM and Top3a. Based on the results obtained in this study, we reached the conclusion that Top3a and BLM are implicated in the decatenation of DNA in newly synthesized sister chromatids. In addition, it has been indicated that BLM and Top3a function cooperatively to suppress the formation of sister chromatid exchange. Finally, epistatic analyses using various gene knockout cells, suggested that BLM functions in the recombination pathway involving XRCC3 under damage induced condition.