Linking histone demethylation and the DNA damage response.

描述(由申请人提供)：这项拟议工作的目标是表征组蛋白去甲基酶LSD1在DNA损伤反应(DDR)中的功能。LSD1已被证明调节许多基因，并在许多不同的生物和病理途径中发挥作用，特别是在癌症中。LSD1的小分子抑制剂已经开始在临床前研究中得到表征；事实上，这些药物显示出作为一种新的表观遗传疗法治疗多种不同类型癌症的前景。然而，LSD1在DDR途径中的功能及其在基因组稳定性中的作用才刚刚开始被发现。结合生物化学、分子生物学和细胞生物学的初步结果显示，LSD1在53BP1肿瘤抑制基因上游的DDR途径中发挥功能。这些结果表明，LSD1通过调节DNA损伤部位的泛素化来实现这一功能。LSD1直接在这一途径中发挥作用并是DDR机制的关键组件的假设将通过一些生化和分子策略进行检验。这里提出的工作将在LSD1的发现者、染色质研究的世界领先者杨石博士的指导下进行。应聘者是医学博士和博士，接受过临床病理学方面的培训，正在寻求基础研究方面的进一步培训。长期目标是建立和指导一个独立的研究实验室，研究染色质在基因组维持中的作用。预计该项目将对基因组稳定性的机制产生重要的洞察力，并将为候选人成为一名独立研究人员做好准备。

DESCRIPTION (provided by applicant): The goal of this proposed work is to characterize the function of the histone demethylase, LSD1, in the DNA damage response (DDR). LSD1 has been shown to regulate many genes and act in a number of distinct biological and pathological pathways, particularly in cancer. Small molecule inhibitors of LSD1 have begun to be characterized in preclinical studies; indeed, these show promise as a novel modality for epigenetic therapy for a number of different types of cancer. However, the function of LSD1 in the DDR pathway and its role in genomic stability is just beginning to be uncovered. Preliminary results, using a combination of biochemistry, molecular biology and cell biology, reveal that LSD1 functions in the DDR pathway upstream of the 53BP1 tumor suppressor. These results demonstrate that LSD1 performs this function by regulation of ubiquitylation at sites of DNA damage. The hypothesis that LSD1 functions directly in this pathway and is a critical component of the DDR machinery will be tested by a number of biochemical and molecular strategies. The work proposed here will be conducted under the mentorship of Dr. Yang Shi, discoverer of LSD1 and a world leader in chromatin research. The candidate is an M.D., Ph.D. with training in clinical pathology and seeks further training in basic research. The long-term goal is to establish and direct an independent research laboratory studying the role of chromatin in genomic maintenance. It is anticipated that the project will yield important insight into the mechanisms of genomic stability and will prepare the candidate for a career as an independent investigator.