Graduation Term

2015

Degree Name

Doctor of Philosophy (PhD)

Department

School of Biological Sciences

Committee Chair

Erik D. Larson

Abstract

Repetitive DNA comprises a majority of the human genome yet functions and overall impacts on site-specific genetic instability are not fully defined. Repetitive G-rich sequences have the propensity to form G-quadruplex (G4), which are stable non-B form DNA structures. G4 structures are conspicuously found at regions of site-specific instability. Even so, human genomic loci capable of forming this structure and their connection to DNA rearrangements are just beginning to be elucidated. My dissertation focuses on G4 structures and their capacity to promote site-specific changes in the human genome, particularly at oncogenes. I identified and investigated new biologically relevant G4 loci in the human genome, using novel computational approaches. The ability for G4 structure formation at subsequent G4 loci was assayed in vitro using multiple complimentary techniques. Using human sequence variation databases, these loci showed evidence of increased mutagenesis on both the small and large-scale. At the experimental level, I focused on the frequently translocated oncogene TCF3 and connected its instability with G4 structure formation. Finally, I examined how factors functioning in a highly conserved repair pathway, mismatch repair, respond to G4 DNA. My results provide new insights into site-specific genetic instability at repetitive guanine sequences, and offer a new perspective on the biological impact of G4 structure formation.

Access Type

Dissertation-Open Access

DOI

http://doi.org/10.30707/ETD2015.Williams.J

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