Author ORCID Identifier
Date Available
10-9-2020
Year of Publication
2019
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
First Advisor
Dr. Guo-Min Li
Abstract
Genomic instability, in the form of gene mutations, insertions/deletions, and gene amplifications, is one of the hallmarks in many types of cancers and other inheritable genetic disorders. Trinucleotide repeat (TNR) disorders, such as Huntington’s disease (HD) and Myotonic dystrophy (DM) can be inherited and repeats may be extended through subsequent generations. However, it is not clear how the CAG repeats expand through generations in HD. Two possible repeat expansion mechanisms include: 1) polymerase mediated repeat extension; 2) persistent TNR hairpin structure formation persisting in the genome resulting in expansion after subsequent cell division. Recent in vitro studies suggested that a family A translesion polymerase, polymerase θ (Polθ), was able to synthesize DNA larger than the template DNA. Clinical and in vivo studies showed either overexpression or knock down of Polθ caused poor survival in breast cancer patients and genomic instability. However, the role of Polθ in TNR expansion remains unelucidated. Therefore, we hypothesize that Polθ can directly cause TNR expansion during DNA synthesis. The investigation of the functional properties of Polθ during DNA replication and TNR synthesis will provide insight for the mechanism of TNR expansion through generations.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2019.394
Funding Information
This dissertation was supported by NRSA Institutional Predoctoral Training Grants (T32: ES007266) and National Institute of Health (NIH) R01 (GM112702).
Recommended Citation
Chan, Kara Y., "MECHANISMS OF TRINUCLEOTIDE REPEAT INSTABILITY DURING DNA SYNTHESIS" (2019). Theses and Dissertations--Toxicology and Cancer Biology. 29.
https://uknowledge.uky.edu/toxicology_etds/29
Included in
Biochemistry Commons, Cell Biology Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Genetic Processes Commons, Genetics Commons, Laboratory and Basic Science Research Commons, Medical Genetics Commons, Molecular Biology Commons, Molecular Genetics Commons, Nervous System Diseases Commons
