Altered Helical Structures: Repair and Induction of Genomic Instability

描述(由申请者提供)：要在当今癌症研究领域做出重大贡献，需要多学科的方法。因此，我选择了一个博士后职位，在那里我可以利用我在有机合成方面的专业知识，并扩大我在生物化学、细胞和分子生物学领域的知识。由于我在格雷泽实验室的工作，我的愿望是利用三链技术作为我研究改变的螺旋结构及其在基因组不稳定中的作用的模型。我的目的是扩大我在DNA修复和细胞凋亡领域的研究。在获奖期结束时，我的目标是过渡到一个终身职位，成为一名拥有既定癌症研究计划的独立科学家。最终，我的长期研究目标是揭开癌症治疗的新策略。 DNA不断暴露在对其结构造成破坏的制剂中，导致重要的遗传信息丢失。为了抵消这种损害的潜在破坏性影响，所有生物体都进化出了各种不同的修复过程。DNA修复的重要性从几种易患癌症的人类遗传疾病的存在中可见一斑，这些疾病是由于其中一条途径的缺陷造成的。能够形成非B构象的自然产生的DNA序列在人类基因组中含量丰富，是遗传不稳定性的来源之一。事实上，这些序列被认为参与了几个与疾病相关的基因的调控，包括人类的c-myc基因。序列特异的DNA结合分子在与双链DNA结合时会导致不寻常的结构形成，将被用作研究这些结构在基因组不稳定中的作用的工具。将检查它们的修复情况，以及它们激活促凋亡途径的能力。这一建议的长期目标是了解DNA损伤识别的分子机制，以及异常或修饰的DNA结构在基因组不稳定中的作用。 相关性：研究表明，自然发生的异常DNA结构在基因表达和基因组不稳定中发挥了作用。对细胞如何代谢这些结构的更多了解将为包括癌症在内的许多人类疾病的发病机制提供洞察力。

DESCRIPTION (provided by applicant): To make a significant contribution to the field of cancer research today requires a multi-disciplinary approach. Thus, I chose to accept a postdoctoral position wherein I could capitalize on my expertise in organic synthesis and expand my knowledge in the areas of biochemistry, cellular and molecular biology. As a result of my work in the Glazer lab, my desire is to utilize triplex technology as a model in my investigation of altered helical structures and their role in genomic instability. It is my intention to expand my research in the areas of DNA repair and apoptosis. At the completion of the award period, it is my goal to have transitioned into a tenured-track position as an independent scientist with an established cancer research program. Ultimately, my long-term research goal is to unveil new strategies for cancer treatment. DNA is continually exposed to agents that cause damage to its structure, resulting in the loss of vital genetic information. To counteract the potentially devastating effects of such damage, all organisms have evolved a variety of different repair processes. The importance of DNA repair is shown by the existence of several cancer-prone human genetic disorders which are a result of defects in one of these pathways. Naturally occurring DNA sequences capable of forming non-B conformations are abundant in the human genome, and represent a source of genetic instability. In fact, these sequences are believed to be involved in the regulation of several disease-linked genes, including the human c-myc gene. Sequence-specific DNA binding molecules, which result in the formation of unusual structures upon binding to duplex DNA, will be used as a tool to study the role of these structures in genomic instability. Their repair will be examined, along with their ability to activate pro-apoptotic pathways. The long-term goal of this proposal is to understand the molecular mechanisms of DNA damage recognition, and the role of unusual or modified DNA structures in genomic instability. Relevance: Studies have shown that naturally occurring unusual DNA structures play a role in gene expression and genomic instability. An increased knowledge of how cells metabolize these structures will provide insight into the pathogenesis of a number of human diseases including cancer.