INFLAMMATION INDUCED CYTOSINE DEAMINATION DAMAGE IN CANCER ETIOLOGY

Cancer is a major health challenge worldwide, and inflammation is thought to be an important factor in cancer etiology. The mutational landscape of human cancer is dominated by cytosine to thymine transition mutations, and the primary mechanism for these mutations is the deamination of cytosine and cytosine analogs to uracil and the corresponding uracil analogs. During replication, uracil and uracil analogs codes as thymine, leading to the aforementioned transition mutation. However, inflammation is known to cause a characteristic guanine to thymine transversion mutation due to the oxidation of guanine to 8-oxoguanine that mispairs with adenine during replication. Herein lies the unsolved conundrum- if inflammation causes guanine to thymine transversion mutations, why is the prevalent mutation observed a cytosine to thymine transition mutation? In my dissertation, I first report a novel method to measure cytosine adducts through enzymatic release by mispair selective glycosylases and analysis by GC/MS/MS. I then propose and model a hypothesis to elucidate how partially redundant and potentially competing DNA repair pathways could be a critical link between oxidative damage and the widely observed cytosine to thymine transition mutations through oligonucleotide studies. Lastly, I extrapolate the method described earlier to Next Generation Sequencing (NGS) experiments and provide the corresponding evidence to support the previous two studies through NGS data. The methods described here will be valuable for understanding DNA damage and repair pathways involved in genetic mutations that drive human cancer, and the applications of these results are vast- ranging from advancements to laboratory procedures to mechanism-based biomarkers for early cancer detection.

Name thesis:degree_name

Cell Biology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2022

Author dc:creator

• Hsu, Chia Wei

• Biology, Cell
• Biology, Genetics
• Biology, Molecular

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12677

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12677