Study of genome instability syndromes

基因组不稳定综合征的研究

基本信息

批准号：
14380323
负责人：
SEKI Masayuki
金额：
$ 8.51万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Werner and Bloom syndrome causative genes, WRN and BLM, encode RecQ helicase. In this study, we addressed the cellular functions of WRN and BLM, and the following results were achieved.1.The function of RECQL1 and RECQL5 that are member of RecQ helicase family, were not known. We have shown that both RECQL1 and RECQL5 have a backup role of BLM in the cell (MCB 2003).2.The evidence that ATM interacts with BLM and phosphorylates BLM under DNA damaged condition implicated functional relationship between both. However, our analysis of DT40 blm, atm, and blm/atm cells, revealed that there is little genetics interaction between the two (Biochim.Biophys.Acta.2004).3.It was shown that the (Fanconi anaemia syndrome) FANC complex interacts with BLM. We reported the existence of functional relationship between FANCC and BLM (EMBO J.2005).4.The analysis of DT40 wrn/xrcc3, wrn/blm, blm/xrcc3, and wrn/blm/xrcc3 mutant cells, revealed that BLM but not WRN belong to homologous recombination repair pathway, which XRCC3 involves (manuscript in preparation).5.SGS1 is budding yeast homologue of WRN and BLM gene. It is well known Sgs1 and BLM interact with DNA topoisomerase III (Top3). We showed that the ability of Sgs1 to interact with Top3 is essential for damage induced homologous recombination in budding yeast (DNA Repair 2005).6.WRNIP1 is a novel protein that interacts with WRN. Using yeast genetics, we analyzed budding yeast counterparts of WRN and WRNIP1, SGS1 and MGS1, respectively. The analysis of sgs1-mgs1 double mutant cells revealed the existence of functional relationship between the two (DNA repair,2002). In addition, Mgs1 genetically interacts with replicative DNA polymerase δ (Mol Genet Genomics,2002;Genes to Cells,2004). Finally, it was shown that human WRNIP1 protein is able to directly bind and stimulate human Polδ activities in the test tube (Genes to Cells,2005).

Werner和Bloom综合征的致病基因WRN和BLM编码RecQ解旋酶。本研究对WRN和BLM的细胞功能进行了研究，取得了以下成果：1.RecQ解旋酶成员RECQL1和RECQL5的功能。我们已经证明 RECQL1 和 RECQL5 在细胞中都具有 BLM 的备份作用（MCB 2003）。2. ATM 与 BLM 相互作用并在 DNA 损伤条件下磷酸化 BLM 的证据表明两者之间存在功能关系。然而，我们对 DT40 blm、atm 和 blm/atm 细胞的分析表明，两者之间几乎没有遗传相互作用 (Biochim.Biophys. Acta.2004).3.结果表明（范可尼贫血综合征）FANC 复合物与 BLM 之间存在功能关系。 FANCC和BLM (EMBO J.2005).4.对DT40 wrn/xrcc3、wrn/blm、blm/xrcc3和wrn/blm/xrcc3突变细胞的分析，发现BLM而非WRN属于同源重组修复途径，其中XRCC3涉及(手稿正在准备)。5.SGS1是出芽酵母WRN和BLM基因的同源物。众所周知，Sgs1 和 BLM 与 DNA 拓扑异构酶 III (Top3) 相互作用。我们表明，Sgs1 与 Top3 相互作用的能力对于芽殖酵母损伤诱导的同源重组至关重要（DNA Repair 2005）。6.WRNIP1 是一种新型相互作用蛋白。利用酵母遗传学，我们分别分析了 WRN 和 WRNIP1、SGS1 和 MGS1 的出芽酵母表亲。 sgs1-mgs1双突变细胞揭示了两者之间存在功能关系（DNA修复，2002）此外，Mgs1与复制DNA聚合酶δ存在遗传相互作用（Mol Genet Genomics，2002；Genes to Cells，2004）。研究表明，人类 WRNIP1 蛋白能够在试管中直接结合并刺激人类 Polδ 活性（Genes to Cells，2005）。