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Dissertation
Characterization of acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2020
DOI:
https://doi.org/10.17918/00000298
Abstract
Fanconi anemia (FA) is a genetic disorder that results in bone marrow failure if not treated by hematopoietic stem cell transplant (HSCT). However, post-transplant FA patients face a high risk for young-onset squamous cell carcinoma, namely esophageal squamous cell carcinoma (ESCC). The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and a major human carcinogen. However, the molecular basis of acetaldehyde-induced genomic instability and SCCs remains elusive. Here we report the effects of acetaldehyde on replication stress response in esophageal cells. Acetaldehyde-exposed esophageal keratinocytes display accumulation of DNA damage foci, S- and G2/M-phase delay, and increased localization of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, indicating that acetaldehyde impedes replication fork progression. Furthermore, FANCD2 depletion exacerbates replication abnormalities and elevates DNA damage, indicating that FANCD2 prevents acetaldehyde-induced genomic instability in esophageal keratinocytes. Moreover, with the emergence of p53 as a negative transcriptional regulator of the Fanconi anemia (FA) DNA repair pathway, we set out to investigate the functional interaction between p53 and the FA DNA repair pathway in ESCC. We found that dominant-negative p53 promotes ESCC cell survival, while FANCD2 depletion imparts crosslink sensitivity on ESCC cells. Additionally, stabilization of p53 increased transcription of p21 mRNA and G1 cell accumulation after acetaldehyde treatment. These studies contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol-related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs.
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Details
- Title
- Characterization of acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes
- Creators
- Jasmine Denice Parnell-Peake
- Contributors
- Eishi Noguchi (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- viii, 179 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014695135404721