NIH Director's Pioneer Award

NPDA第1页Titia de Lange DNA损伤反应的新途径 意义 对DNA损伤的生物学反应是现代生物学中的一个中心问题， 优秀调查员的注意。生命的延续取决于细胞保护自身的能力。 DNA的内在和外在损伤以及DNA损伤反应的缺陷可能有助于 肿瘤发生、衰老、遗传性疾病和生育问题。所有的真核细胞都会对 DNA断裂（DSB）和其他病变通过一个信号通路，控制细胞周期的进展， 控制着DNA修复的各个方面。信息流由一组蛋白激酶携带，如ATM， ATR，Chk 1和Chk 2，来自酵母遗传筛选和人类染色体研究 破损综合征虽然信号转导的机制和至少一些靶点， 这些激酶是已知的，我们不知道DNA损伤是如何检测的，也不知道这种传感的参与者是谁。 步骤在很大程度上仍然是未知。 为了使该领域履行其改善人类健康的承诺，DNA的研究 损伤检测需要一个新的方向。在这里，我描述了我的计划，以迫使我们的转折点， 获取这方面的知识。这些实验旨在解决主要的突出问题， 该领域的问题：激活通路的信号是什么（例如DNA末端，改变的DNA 结构，或改变的核小体构型），如何感知信号（哪些新的或已知的蛋白质 是第一个到达病变的人），以及传感器如何与已知的传感器接口 pathway？ 当前方法的局限性 目前可用于研究哺乳动物DNA损伤反应的技术有三个主要方面： 缺点：在分子标记的缺乏，

NPDA page 1 Titia de Lange A new approach to the DNA damage response Significance The biological response to DNA damage is a central issue in modern biology that has attracted the attention of outstanding investigators. The continuity of life depends on the ability of cells to protect their DNA from intrinsic and extrinsic damage and deficiencies in the DNA damage response can contribute to tumorigenesis, aspects of aging, hereditary disorders, and fertility problems. All eukaryotic cells respond to DNA breaks (DSBs) and other lesions through a signaling pathway that governs cell cycle progression and controls aspects of DNA repair. The information flow is carried by a set of protein kinases, such as ATM, ATR, Chk1, and Chk2, that emerged from genetic screens in yeast and studies of human chromosome breakage syndromes. Although the mechanism of signal transduction and at least some of the targets of these kinases are known, we do not know how DNA damage is detected and the players in this sensing step have remained largely unknown. In order for the field to fulfill its promise for the improvement of human health, the study of DNA damage sensing needs to take a new direction. Here I describe my plans to force an inflection point in our acquisition of knowledge in this area. The experiments are designed to address the major outstanding questions in the field: what is the signal that activates the pathway (e.g. a DNA end, an altered DNA structure, or an altered nucleosomal configuration), how is the signal sensed (which new or known proteins are the first to arrive at the lesion), and how do the sensors interface with the known transducers of the pathway? Limitations of the current approaches The technology currently available to study the mammalian DNA damage response has three major drawbacks: the absence of a molecular mark at the