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iDEA: DREXEL LIBRARIES E-REPOSITORY AND ARCHIVES

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Investigating acetaldehyde-induced DNA protein crosslinks in esophageal cells

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Title
Investigating acetaldehyde-induced DNA protein crosslinks in esophageal cells
Author(s)
Lin, Baicheng
Advisor(s)
Noguchi, Eishi; Sell, Christian
Keywords
Molecular biology; Cytology; Genetics; Acetaldehyde; Proteins--Crosslinking
Date
2018-06
Publisher
Drexel University
Thesis
M.S., Molecular and Cell Biology and Genetics -- Drexel University, 2018
Abstract
Chronic alcohol consumption is a world-wide health problem, leading to a variety of adverse health issues. The primary metabolite of alcohol, acetaldehyde, is a major carcinogen that can cause DNA damage and is thought to increase the risk of esophageal cancer (EC). EC is one of the serious cancers ranking as the eighth most common cancer in the world. Its five-year survival rate is less than 20%. EC is mainly classified into two types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EA). Studies showed that chronic alcohol consumption increases the risk of ESCC in individuals with the ALDH2*2 (E487K) allele. The ALDH2*2 subunit impairs the tetramer enzymatic activity. Thus, the catalytic activity of the enzyme containing ALDH2*2 subunit is less than wild-type (ALDH2*1/*1), resulting in acetaldehyde accumulation in digestive organs, such as upper aerodigestive tract (UADT), stomach, and gut. 1 The liver is also commonly affected by ethanol since ethanol metabolism mainly occurs in this organ.2 Acetaldehyde accumulation causes DNA adduct formation, such as DNA-protein crosslinks (DPCs). DPCs impede DNA transactions which induces DNA double-stranded breaks (DSBs). A specific repair mechanism is required to cope with DPCs because canonical DNA repair pathways, such as homologous recombination (HR), nucleotide excision repair (NER), and translesion synthesis (TLS), cannot efficiently remove the DPCs. Recent studies reported that a protease called Spartan recognizes cross-linked proteins and contributes to survival of DPCs-harboring cells. In this report, we used the human esophageal cancer cell line TE11 as a model to investigate the effects of acetaldehyde on genomic integrity. To sensitize TE11 cells to acetaldehyde, we treated cells with the ALDH2 inhibitor disulfiram before acetaldehyde exposure. This treatment reduced TE11 cell viability and allowed us to investigate how acetaldehyde induces genomic instability. To investigate the role of Spartan protease in the repair of acetaldehyde-induced DPCs, we depleted Spartan in TE11 cells using RNAi technology. Spartan-depleted TE11 cells showed hypersensitivity to acetaldehyde and an increased level of DNA damage represented by 53BP1 DNA repair foci. The rapid approach to DNA adduct recovery (RADAR) assay revealed that Spartan-depleted TE11 cells displayed elevated levels of DPCs after acetaldehyde exposure when compared to control cells. These results suggest that Spartan protease is involved in the repair of acetaldehyde-induced DPCs.
URI
http://hdl.handle.net/1860/idea:8024
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