Year: 2018
Type: dissertation
Abstract: CTG/CAG repeat expansions cause at least 16 neurodegenerative and neuromuscular diseases. Unusual DNA slip-out structures that form in CTG/CAG repeat tracts have been implicated in the expansion process; targeting these structures may be of therapeutic benefit. In vitro assays can be used to screen for DNA-binding molecules that specifically target disease-associated slip-out structures and therefore potentially modulate expansions. Toward establishing tool compounds, we characterized the effects of ethidium bromide and actinomycin D on repeat DNA metabolism in vitro. Both tool compounds preferentially bound certain CTG/CAG structures over others, consistent with the varying efficiencies with which they inhibited the repair of different slip-out substrates. Additionally, I screened small molecules designed to bind RNA repeat disorder sequences, which are suggested lead compounds. Multiple compounds inhibited slipped-DNA repair, marking them as potential modulators of instability. However, the same compounds also inhibited G-T base-base mismatch repair, indicating possible off-target, genotoxic effects.
Source: TSpace (University of Toronto)
Author: Karen Chiang
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3155088798