Mechanisms of Mitotic Recombination

在此输入文本，它是您的应用程序的新摘要信息。此部分必须为no 超过30行的文本。 有丝分裂交叉是有害的，因为它会导致杂合性或染色体的丧失。 重排，两者都与癌症有关。有丝分裂互换的危险在于 在布鲁姆综合征患者中表现明显，这是一种罕见的遗传性疾病，其特征是高度 一系列恶性肿瘤的发病率升高和发病早。细胞的一个主要特征 这些患者的姐妹染色单体之间的有丝分裂交叉升高，同源 染色体和异源染色体。编码RecQ解旋酶的BLM的研究， 为细胞用来防止有丝分裂交叉的机制提供了重要的见解。我们 通过利用果蝇的独特优势为这些洞察力做出了重大贡献 作为BLM细胞功能遗传和分子研究的后生动物模型 解旋酶。我们建立了一个详细的果蝇DmBLm在双核细胞中的功能模型。 链断裂修复；我们现在将测试此模型的预测，以及 其他的，使用已建立的和新的分子遗传分析。这包括设计新的分析方法。 用于培养的人类细胞。尽管修复双链断裂可能导致交叉， 大多数自发的有丝分裂交叉被认为是由复制分叉的问题引起的， 包括分叉级数的块、断叉和一些分叉收敛。基于我们的 DmBLM和三种结构特异性DNA中任一种时发生的致死表型的研究 没有核酸内切酶，我们已经修改了模型来解释DmBLM在复制分叉中的作用 修复；我们将使用创新的方法来测试这些模型的关键预测。我们还将结合 体内和体外研究以揭示这三种内切酶(MUS81-MMS4， Gen，和MUS312-SLX1)，其中每一个都与Holliday连接的解决有关 中间体。重要的是，我们发现Gen，它似乎只在 萌芽酵母在果蝇中有几个重要的功能，它不存在于分裂酵母中。我们的 因此，研究将有助于更好地了解这种酶的细胞功能和 其他推定的解决方案。最后，我们将确定其他基因/蛋白质参与预防或 通过研究候选基因和通过物理相互作用促进有丝分裂交叉 实验。我们建议的研究结果将加强我们对机制的理解 有丝分裂交叉是通过什么产生的，以及细胞如何利用肿瘤抑制蛋白 BLm和其他蛋白质防止有丝分裂交叉，以及如何推测Holliday连接 解析函数，促进交叉。

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Mitotic crossing over is detrimental because it can lead to loss of heterozygosity or chromosome rearrangement, both of which are associated with cancer. The dangers of mitotic crossing over are evident in persons with Bloom syndrome, a rare, hereditary disease characterized by a highly elevated incidence and early onset of a broad range of malignancies. A predominant feature of cells from these patients is elevated mitotic crossing over between sister chromatids, homologous chromosomes, and heterologous chromosomes. Studies of BLM, which encodes a RecQ helicase, are providing important insights into mechanisms cells use to prevent mitotic crossing over. We have made significant contributions to these insights by exploiting unique advantages of Drosophila as a model metazoan for genetic and molecular studies of the cellular functions of the BLM helicase. We have developed a detailed model for the function of Drosophila DmBLM in double- strand break repair; we will now test predictions of this model, as well as models proposed by others, using established and novel molecular genetic assays. This includes novel assays designed for use in cultured human cells. Although repair of double-strand breaks may lead to crossing over, most spontaneous mitotic crossovers are thought to arise from problems at the replication fork, including blocks to fork progression, broken forks, and some fork convergences. Based on our studies of lethal phenotypes that occur when both DmBLM and any of three structure-specific DNA endonuclease is absent, we have modified models to explain roles of DmBLM in replication fork repair; we will use innovative methods to test key predictions of these models. We will also combine in vivo and in vitro studies to uncover functions of these three endonucleases (MUS81-MMS4, GEN, and MUS312-SLX1), each of which has been implicated in resolution of Holliday junction intermediates. Importantly, we find that GEN, which appears to play only a secondary role in budding yeast and is absent from fission yeast, has several important functions in Drosophila. Our studies will therefore lead to a greater understanding of the cellular functions of this enzyme and the other putative resolvases. Finally, we will identify additional genes/proteins involved in preventing or promoting mitotic crossovers through studies of candidate genes and through physical interaction experiments. The results from our proposed studies will enhance our understanding of mechanisms through which mitotic crossovers are generated and how cells employ the tumor suppressor protein BLM and other proteins to prevent mitotic crossing over, and how putative Holliday junction resolvases function to promote crossing over.