Linking histone demethylation and the DNA damage response.

将组蛋白去甲基化和 DNA 损伤反应联系起来。

• 批准号: 8091922
• 负责人: NIMA MOSAMMAPARAST
• 金额: $ 17.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-17 至 2012-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091922
• 关键词: Address; Basic Science; Biochemical; Biochemistry; Biological; Cell Cycle Checkpoint; Cells; Cellular biology; Chromatin; Clinical Pathology; Complex; DNA; DNA Damage; DNA Repair; Data; Development; Doctor of Medicine; Doctor of Philosophy; Epigenetic Process; Genes; Genome; Genome Stability; Genomics; Goals; Grant; Histone Deacetylase; Histones; Human; K-Series Research Career Programs; Laboratory Study; Lead; Light; Link; Lysine; Maintenance; Malignant Neoplasms; Mammalian Cell; Mentorship; Methylation; Modality; Modification; Molecular; Molecular Biology; Nucleosomes; Pathway interactions; Phenocopy; Play; Post-Translational Protein Processing; Process; Proteins; Recruitment Activity; Regulation; Research; Research Personnel; Role; Signal Transduction; Site; Testing; Training; Transcription Repressor/Corepressor; Transcriptional Regulation; Tumor Suppressor Proteins; Work; Yang; base; cancer type; career; demethylation; design; in vivo; inhibitor/antagonist; insight; novel; novel diagnostics; novel therapeutics; overexpression; preclinical study; repaired; research study; response; small molecule; tumor; ubiquitin ligase

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. PUBLIC HEALTH RELEVANCE: The research proposed in this grant has significance for the way in which cells guard their genome, a pathway important for cancer development. The proposed studies will shed light on the molecular mechanisms in this pathway, and may lead to novel diagnostic and therapeutic avenues in cancer.

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化酶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起作用，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被表征；事实上，这些都显示了作为一种新的表观遗传疗法治疗许多不同类型癌症的前景。然而，LSD1在DDR通路中的功能及其在基因组稳定性中的作用才刚刚开始被揭示。结合生物化学、分子生物学和细胞生物学的初步研究结果表明，LSD1在53BP1抑癌基因上游的DDR通路中起作用。这些结果表明，LSD1通过调控DNA损伤位点的泛素化来实现这一功能。LSD1直接在这一途径中起作用，并且是DDR机制的关键组成部分的假设将通过一系列生化和分子策略进行测试。这里提出的工作将在LSD1的发现者、世界染色质研究的领导者杨石博士的指导下进行。该候选人是医学博士、博士，接受过临床病理学培训，并寻求进一步的基础研究培训。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见解，并将为候选人作为独立研究者的职业生涯做好准备。