DNA double-strand break repair, chromosome translocations and cancer

产生了促进肿瘤发生的遗传损伤，包括染色体重排。 主要是通过非法的DNA修复。在这次续期申请中，我们将继续调查病理 异常DNA双链断裂(DSB)修复的后果。这一高度协作和集成的 计划将阐明DNA序列、染色质可及性和核组织如何影响命运 DSB的病理转归与细胞类型和细胞周期有关。我们将继续使用 酵母和小鼠模型中的遗传学、生物化学和细胞生物学的结合。NEXT的应用 代技术与高通量基因组学方法一起提供了前所未有的财富 关于癌症基因组中基因组不稳定性的信息。我们建议利用我们多方面的 具有强大的基因组学和计算生物学组件的实验方法 程序。拉巴丹和贝尔博士将研究突变特征--DNA的统计丰富模式 替换和重排在肿瘤中普遍存在--与特定的BRCA1缺陷相关。他们 还将表征由其他三个项目生成的突变签名。总的来说，这些数据将会有所帮助 解开人类肿瘤复杂的突变图景。赛明顿博士和西西亚博士将在 引起染色体重排的起始DNA损伤的性质，重点是DNA复制错误 在修复缺陷的酵母和基因组编辑的哺乳动物细胞中。沙博士将在当地连接染色质的可访问性 在全球范围内，由于其破裂和产生易位的倾向； 淋巴细胞成熟过程中的免疫球蛋白和T细胞受体基因座促进了淋巴瘤的发生。具体来说， 查博士将阐明ATM缺陷如何以依赖于细胞类型和细胞周期的方式有利于易位。 最后，Gautier博士和Gottesman博士将研究细胞核的空间组织如何调节DNA修复。 具体地说，他们将确定Wiskott-Aldrich综合征中的核肌动蛋白和WASP基因是如何突变的， 允许切除并影响DSB或由以下因素引发的遗传毒性损害后的染色体易位 拓扑异构酶抑制。这四个项目将得到两个科学核心的支持。所有领导者和共同领导者 有很强的协作历史和卓有成效的记录。

The genetic lesions that promote tumorigenesis, including chromosomal rearrangements, are generated primarily by illegitimate DNA repair. In this renewal application, we will continue to investigate the pathological consequences of aberrant DNA double-strand break (DSB) repair. This highly collaborative and integrated program will elucidate how DNA sequence, chromatin accessibility and nuclear organization influence the fate and pathological outcomes of DSBs in a cell type and cell cycle dependent manner. We will continue to use a combination of genetics in yeast and mouse models, biochemistry and cell biology. The application of next generation technologies together with high-throughput genomics approaches provides an unprecedented wealth of information about genomic instability in cancer genomes. We propose to leverage our multifaceted experimental approach with the strong genomics and computational biology components that pervade the Program. Drs. Rabadan and Baer will study mutation signatures - the statistically enriched patterns of DNA substitutions and rearrangements common across tumors - associated with specific BRCA1 deficiencies. They will also characterize mutation signatures generated by the other three Projects. Collectively these data will help deconvolute the complex mutational landscape of human tumors. Drs. Symington and Ciccia will address the nature of the initiating DNA lesions resulting in chromosome rearrangements, focusing on DNA replication errors in repair-deficient yeast and genome-edited mammalian cells. Dr. Sha will connect chromatin accessibility, locally and globally, with its propensity to break and yield translocations; pathological translocations at the immunoglobulin and T cell receptor loci during lymphocyte maturation fuel lymphoma development. Specifically, Dr. Zha will elucidate how ATM deficiencies favor translocations in a cell type and cell cycle dependent manner. Finally, Drs. Gautier and Gottesman will study how the spatial organization of the nucleus modulates DNA repair. Specifically, they will determine how nuclear actin and WASP, the gene mutated in Wiskott-Aldrich Syndrome, enables resection and influences chromosome translocations following DSBs or genotoxic lesions triggered by topoisomerase inhibition. The four Projects will be supported by two scientific Cores. All leaders and co-leaders have a strong history and record of productive collaboration.