Grant: Project Grant

The human genome, the blueprint for every cell, is encoded by over 3 billion base pairs of DNA. To fit this large amount of DNA into the nucleus, it needs to be condensed into chromatin. In this structure, DNA is wrapped around histone octomers to form nucleosomes that tightly pack together. However, this condensed chromatin creates a barrier to essential cellular DNA metabolism processes, including replication, transcription, and damage repair. Chromatin remodelers are ATPase enzymes that interact with other proteins to regulate and control the access of DNA metabolism machinery to DNA by altering the compaction of DNA. The human protein HELLS is a chromatin remodeler that, in normal cells, plays essential roles in establishing the most condensed form of chromatin, called heterochromatin, and regulating access to heterochromatin to facilitate processes such as DNA transcription for cell growth and proliferation, and DNA damage repair. However, HELLS is mutated in a rare disease called ICF-4, is overexpressed in many cancers, and a role for HELLS in regulating the ability of cancer cells to maintain a stem cell-like state or differentiate into more mature cells has been established. As such, HELLS is a potential target to develop new cancer therapies. The aim of this research project is to use integrated biochemical, structural biology, and cell biology assays to determine the molecular mechanisms for how HELLS is regulated by protein interaction partners and post-translational modifications, which are chemical modifications of proteins that occur after they are made. Results from the project will deepen our fundamental understanding of the essential cellular processes HELLS is involved in, provide insights into how regulation and malfunctioning of HELLS contributes to diseases including cancer, and provide a molecular basis to design therapies targeting HELLS to treat cancer.