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.
A complete copy of the human genome is packaged inside every cell of our body by wrapping around histone proteins. Small chemical 'epigenetic'tags on both DNA and histones help regulate the accessibility of the genetic information encoded within our DNA, controlling whether certain genes are switched on or off. The patterning of epigenetic tags in cancer cells is often changed, and increasing evidence suggests these changes may be underlying causes of malignant transformation. By gaining a basic understanding of how epigenetic tags are regulated, this proposal aims to learn new ways in which normal human cells become cancerous and identify new cellular targets for cancer treatment and prevention. The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
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