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脱甲基酶LSD 1在DNA损伤反应（DDR）中的功能。LSD 1已被证明可以调节许多基因，并在许多不同的生物学和病理学途径中起作用，特别是在癌症中。LSD 1的小分子抑制剂已经开始在临床前研究中被表征;事实上，这些显示出作为许多不同类型癌症的表观遗传疗法的新模式的希望。然而，LSD 1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。使用生物化学、分子生物学和细胞生物学的组合的初步结果显示，LSD 1在53 BP 1肿瘤抑制因子的DDR通路上游发挥作用。这些结果表明，LSD 1通过调节DNA损伤位点的泛素化来执行此功能。LSD 1直接在该通路中发挥作用并且是DDR机制的关键组成部分的假设将通过许多生化和分子策略进行测试。这里提出的工作将在LSD 1的发现者和染色质研究的世界领导者杨石博士的指导下进行。候选人是医学博士博士在临床病理学的培训，并寻求进一步的培训，在基础研究。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护中的作用。预计该项目将对基因组稳定性的机制产生重要的见解，并为候选人作为独立研究者的职业生涯做好准备。

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.