Graduate Thesis Or Dissertation


Applications and Implementation of Nucleosomal Supergroove Binders for Biochemical Study Public Deposited
  • Nucleosomes are molecular spools composed of an octameric core of histones that binds and wraps ~147 base pairs (bp) of DNA into a tight superhelical coil. They are the fundamental structural unit of all eukaryotic chromosomes, and consequently, many nuclear proteins possess binding motifs specific for nucleosomal recognition. Notable nucleosome-specific binding sites include the acidic patch on the nucleosomal surface, as well as histone tail residues for post-translational modification (PTM). The winding of DNA around the histone octamer also produces another recognition motif called a ‘supergroove’. This motif aligns major and minor grooves that are ~80 bp apart on linear DNA into quasi-continuous supergrooves spanning two gyres of the DNA superhelix. Recently, it has been shown that some transcription factors (TFs) may prefer binding nucleosomal DNA in a transgyre fashion, signifying that the nucleosomal supergroove could potentially serve as an important molecular recognition platform. Each supergroove is composed of 10-12 bp of solvent-accessible DNA compared to 5-6 consecutive bp of a single gyre. Therefore, the alignment of DNA sequences from adjacent gyres essentially magnifies the degree of specificity with which a supergroove-binding ligand can complex with a nucleosome. Since such a ligand would effectively cross-brace both DNA gyres, this immediately suggests a nucleosome-stabilizing function for supergroove binders. This study focuses on the implementation of pyrrole-imidazole polyamides (PIPs) as supergroove binders as well as the viability of an alternative, zinc-finger-based solution. The results provide novel insight for the development of reagents that can serve as sequence-specific chaperones for structural/mechanistic studies of nucleosomal systems.

Date Issued
  • 2022-11-30
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Last Modified
  • 2024-01-08
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