Study of genome instability syndromes

Werner and Bloom综合征致病基因WRN和BLM编码RecQ解旋酶。在本研究中，我们对WRN和BLM的细胞功能进行了研究，得到了以下结果：RECQL1和RECQL5是RecQ解旋酶家族的成员，其功能尚不清楚。我们已经证明RECQL1和RECQL5在细胞中都有BLM的备份作用（MCB 2003）。在DNA损伤条件下，ATM与BLM相互作用并使BLM磷酸化的证据暗示了两者之间的功能关系。然而，我们对DT40 blm、atm和blm/atm细胞的分析显示，两者之间几乎没有遗传相互作用（Biochim.Biophys.Acta.2004）。研究表明（范可尼贫血综合征）FANC复合物与BLM相互作用。我们报道了FANCC和BLM之间存在函数关系（EMBO J.2005）。通过对DT40 wrn/xrcc3、wrn/blm、blm/xrcc3、wrn/blm/xrcc3突变细胞的分析，发现blm属于同源重组修复途径，而wrn不属于同源重组修复途径，而xrcc3参与其中（稿件正在准备中）。SGS1是芽殖酵母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。我们发现Sgs1与Top3相互作用的能力对于出芽酵母损伤诱导的同源重组至关重要（DNA Repair 2005）。WRNIP1是一种与WRN相互作用的新型蛋白。利用酵母遗传学，我们分别分析了WRN和WRNIP1、SGS1和MGS1的芽殖酵母对应物。对sgs1-mgs1双突变细胞的分析揭示了两者之间存在功能关系（DNA修复，2002）。此外，Mgs1基因与复制DNA聚合酶δ相互作用（Mol Genet Genomics,2002;Genes to Cells,2004）。最后，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）。

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).