Genotoxicity Disrupts Intestinal Proliferating Cells

Li, Yingxing

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https://hdl.handle.net/2142/100010 Copy

Description

Title

Genotoxicity Disrupts Intestinal Proliferating Cells

Author(s)

Li, Yingxing

Contributor(s)

Lieu, D'Feau

Issue Date

2018-04

Keyword(s)

• Microbiology
• Genotoxicity
• bacterial toxin
• chemotherapeutics

Abstract

Many bacterial infections have been shown to cause DNA damage in host cells, and a number of pathogens can directly damage host DNA by producing genotoxins. Due to the importance of maintaining genomic integrity for cellular function, cells possess a coordinated DNA damage response (DDR) mechanism to sense damage in DNA and generate a signal amplification cascade to activate DNA repair mediators. Our study has shown that cytolethal distending toxins (CDTs), a genotoxin secreted by mucosal pathogenic bacteria, is responsible for DNA damage and thus prolonged cell cycle arrest in intoxicated intestinal proliferating crypt cells. Our data support that CDT intoxication results in a large increase in activated H2AX level, an early DNA damage signal, and in cellular p53 levels, a major cellular protein responsible for cell cycle arrest in response to DNA damage. Also, we found that CDT-mediated DNA damage results in reduction of a transcription factor involved in the differentiation potential of intestinal proliferating cells, Snai1, which is responsible for lineage allocation in differentiating cells. In order to evaluate whether pathogen-independent DNA damaging agents can lead to reduction in cellular levels of Snai1 in normal human intestinal proliferating cells, used three DNA damage agents, including 5-fluorouracil and etoposide, each of which causes DNA damage in different ways. Our data support that CDT-independent DNA damage lead to dose-dependent reduction in Snai1 level. These experiments enhance our understanding of potential side effects of widely used chemotherapeutics on epithelial barrier homeostasis and overall innate immunity.

Type of Resource

image

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http://hdl.handle.net/2142/100010

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Copyright 2018 Yingxing Li

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