Mechanisms Regulating DNA Methylation Maintenance in Chromatin

染色质 DNA 甲基化维持的调节机制

• 批准号: 9061649
• 负责人: Scott Rothbart
• 金额: $ 24.87万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061649
• 关键词: Aberrant DNA Methylation; Address; Affect; Attention; Binding; Biological; Biological Process; Biology; Cancerous; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chemicals; Chromatin; Chromatin Structure; Colonic Neoplasms; CpG dinucleotide; DNA; DNA Damage; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; DNA Repair; DNA biosynthesis; Daughter; Defect; Dependence; Development; Epigenetic Process; Foundations; Functional disorder; Genetic Transcription; Genomics; Goals; Histone Code; Histone H3; Histones; Human; Human Engineering; Human Genome; Hypersensitivity; In Vitro; Learning; Link; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mentorship; Neoplasm Metastasis; Pattern; Plants; Post-Translational Protein Processing; Proteins; Reading; Research; Resolution; Role; S Phase; Solid; Switch Genes; Systems Biology; Therapeutic; Training; Tumor Cell Line; Tumor Suppressor Genes; Uncertainty; Validation; Writing; cancer cell; cancer initiation; cancer prevention; cancer therapy; career; cellular targeting; epigenetic regulation; genetic information; homeodomain; inhibitor/antagonist; methylation pattern; non-histone protein; programs; protein protein interaction; screening; small molecule inhibitor; therapeutic target; tool; tumor progression; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT DNA methylation and histone post-translational modifications (PTMs) elicit influence on chromatin-templated biological processes, and these `epigenetic' marks are often aberrantly regulated in cancers. Elucidation of mechanisms controlling DNA methylation and histone PTMs are therefore important to better our understanding of the role of epigenetics in cancer. The E3 ubiquitin ligase UHRF1 is genetically linked to the maintenance of cellular DNA methylation and deregulation of UHRF1 correlates with cell proliferation, metastasis, and hypersensitivity to DNA damaging agents. These recent connections of UHRF1 to the regulation of DNA methylation and cancer progression suggest this protein may be a favorable therapeutic target. Yet, many fundamental aspects of UHRF1 biology are not known. The overarching goal of this K99/R00 proposal is therefore to advance our understanding of the interaction of UHRF1 with chromatin and the regulation of DNA methylation inheritance. My preliminary studies established that recognition of methylated histone H3 at lysine 9 by the UHRF1 tandem Tudor domain is required for its DNA methylation maintenance function. Studies in this proposal will build upon these findings to: 1) define how multivalent chromatin engagement drives the DNA methylation maintenance function of UHRF1, 2) determine the spatial and temporal contribution of UHRF1 to DNA methylation maintenance, 3) define the UHRF1 interactome, and 4) develop chemical probes as tools to study UHRF1 function. This proposal is supported by a strong mentorship and training plan, building a solid foundation for a successful independent research career investigating the regulation of the epigenetic program and how its dysfunction leads to the initiation and progression of cancer.

项目总结/文摘