Etiology of Chromosome Translocations

描述（由申请人提供）：染色体易位经常与许多类型的血癌和儿童肉瘤有关。在临床上，染色体易位很重要，因为它们提供了精确诊断癌症类型和定制治疗的能力。巧合的是，导致染色体易位的分子机制还不清楚。现有的证据表明修复DNA双链断裂的过程在染色体易位形成中的作用。最近，我们开发了一种新的酵母为基础的模型系统来检测非同源末端连接（NHEJ）依赖的，相互染色体易位在体内。该系统使我们能够在真实的时间内检测到来自细胞群体的位点特异性DNA双链断裂的相互易位。使用我们的系统进行的筛选导致鉴定出几种提高NHEJ依赖性染色体易位频率的基因突变。通过这个系统，我们发现了特定DNA损伤监测途径在抑制染色体易位中的作用。这项建议的重点是识别和表征抑制染色体易位的遗传网络。结合遗传学，细胞生物学和生物化学的方法将用于提供NHEJ介导的染色体易位的遗传和机制基础的机制见解。这些研究将揭示导致人类染色体易位的分子机制，并可能为治疗或预防血癌的先进疗法提供概念基础。公共卫生相关性：我们研究计划的长期目标是剖析致癌染色体易位的分子机制。我们的研究所确定的基因突变是已知的DNA损伤监测途径，这可以抑制染色体易位，并使患者容易染色体易位和淋巴恶性肿瘤。该应用将识别和表征抑制染色体易位的损伤监视和其他机制，以了解血癌中的缺陷并开发新的预防和/或治疗策略。

DESCRIPTION (provided by applicant): Chromosome translocations are frequently associated with many types of blood cancers and childhood sarcomas. Clinically, chromosome translocations are important because they offer the ability to precisely diagnose the type of cancers and to tailor treatment. Paradoxically, the molecular mechanism that leads to chromosome translocations is not well understood. The available evidence suggests the role of process repairing DNA double strand breaks in the formation of chromosome translocations. Recently, we developed a novel yeast-based model system to detect non-homologous end joining (NHEJ)- dependent, reciprocal chromosome translocations in vivo. This system allowed us to detect in real time a reciprocal translocation of site-specific DNA double strand breaks from a population of cells. A screen using our system resulted in the identification of several gene mutations that elevate the frequency of NHEJ- dependent chromosome translocations. Through this system, we uncovered a role of a specific DNA damage surveillance pathway in suppression of chromosome translocations. The focus of this proposal is to identify and characterize the genetic network that suppresses chromosome translocation. An approach combining genetics, cell biology and biochemistry will be used to provide mechanistic insights into genetic and mechanistic underpinnings of NHEJ-mediated chromosome translocations. These studies will shed light on the molecular mechanism leading to chromosome translocations in humans and may provide conceptual basis for advanced therapeutics to treat or prevent blood cancers. PUBLIC HEALTH RELEVANCE: The long-term objective of our research program is to dissect the molecular mechanism that causes oncogenic chromosome translocations. Mutations of genes identified by our study are known to enforce one of the DNA damage surveillance pathways, which can suppress chromosome translocations, and predispose patients to chromosomal translocations and lymphoid malignancy. This application will identify and characterize damage- surveillance and other mechanisms that suppress chromosome translocation to understand the defects in blood cancers and develop novel preventive and/or therapeutic strategies.