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Thesis
Roles of Timeless in preventing acetaldehyde-mediated DNA damage and promoting esophageal carcinogenesis
Master of Science (M.S.), Drexel University
Jun 2018
DOI:
https://doi.org/10.17918/D8266C
Abstract
Alcohol consumption is linked to the development of esophageal squamous-cell carcinoma (ESCC). Once consumed, alcohol is oxidized into acetaldehyde, leading to a variety of DNA lesions, including interstrand crosslinks and DNA-protein crosslinks. These lesions interfere with the DNA replication process, ultimately leading to DNA double-stranded breaks. Timeless, a component of the replication fork protection complex, aids in stabilizing the DNA replication fork and preserving genomic stability in response to agents that block DNA replication or cause DNA damage. Recently, evidence suggests that Timeless is directly involved in the repair of DNA double-stranded breaks (DSBs). Timeless has also been implicated in the progression of various cancers. However, precise roles of Timeless in DNA repair pathways and tumorigenesis remain elusive. In this study, we investigated the role of Timeless in acetaldehyde-mediated genomic instability and cancer phenotypes. We show in esophageal cancer cells that Timeless depletion results in increased sensitivity to acetaldehyde exposure. Chk1 phosphorylation is increased following Timeless knockdown, indicating activation of DNA damage response signaling. Acetaldehyde exposure also led to ubiquitination of FancD2 especially when Timeless was depleted, suggesting that the Fanconi Anemia DNA repair pathway is activated due to DNA damage caused by Timeless depletion and acetaldehyde treatment. Consistently, Timeless-depleted cells display elevated levels of 53BP1 and BRCA1 DNA repair foci formation upon acetaldehyde exposure. Furthermore, DSB-repair assays using GFP reporter cassettes reveal that Timeless is involved in both non-homologous end joining and homologous recombination pathways. Interestingly, anchorage-independent growth and epithelial-mesenchymal transition, two fundamental characteristics of cancer cells, are positively regulated by Timeless, suggesting that Timeless act as a pro-tumor factor. Considering that cancer cells experience elevated levels of genomic instability, our results suggest the role of Timeless in enhancing DNA repair capacity to support cancer cell growth.
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Details
- Title
- Roles of Timeless in preventing acetaldehyde-mediated DNA damage and promoting esophageal carcinogenesis
- Creators
- Alyssa Duffy - DU
- Contributors
- Eishi Noguchi (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 57 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 8119; 991014632276004721