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Title:DNA damage disrupts intestinal crypt homeostasis
Author(s):Li, Yingxing; Crowder, Molly; Lieu, D'Feau; Enkhbaatar, Michidmaa; Blanke, Steven R.
Contributor(s):Crowder, Molly; Blanke, Steven Robert
DNA damage
Intestinal homeostasis
Abstract:Many bacterial pathogens have been shown to directly damage host DNA during infection by producing genotoxins. To maintain genomic integrity, cells possess DNA damage response mechanism to sense damaged DNA and generate signal amplification cascade that activates DNA repair proteins. Our studies have shown that cytolethal distending toxin (CDT), a genotoxin secreted by gram-negative bacteria, can damage host DNA, and trigger cell cycle arrest in proliferating intestinal crypt cells. Our data shows that CDT intoxication activates DNA damage response, leading to an increase in cellular p53 level, which regulates cell fate in response to stress. Also, we found that CDT-mediated DNA damage results in dose-dependent reduction of cellular SNAI1 level, a transcription factor involved in lineage allocation. Further, we used three DNA-damaging chemotherapeutic agents: bleomycin, 5-fluorouracil and etoposide, each of which causes DNA damage in different ways, and found these reduce Snai1 levels in a dose-dependent manner. To study the impact of DNA damage on intestinal epithelium, we used a mini-organ system, to compare how different populations of intestinal epithelial cells are affected and how this impacts intestinal morphology. We found that proliferating cells, compared to non-proliferating cells, are more sensitive to CDT, 5-fluorouracil and etoposide. We hypothesize that sensitivity of proliferating crypt cells to CDT-mediated DNA damage will result in global changes to lineage allocation and barrier integrity of the intestinal epithelium. These experiments enhance our understanding of the effects of CDT and widely used chemotherapeutics on intestinal crypt cells and epithelial barrier homeostasis.
Issue Date:2019-04-22
Genre:Presentation / Lecture / Speech
Rights Information:Copyright 2019 Yingxing Li, Molly Crowder, D’FeauLieu, Michidmaa Enkhbaatar and Steven R. Blanke
Date Available in IDEALS:2019-04-22

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