The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury
Name
Yu-2016-The Mbd4 DNA glycosy.pdf
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Author(s)
Yu, Amy Marie
Calvo, Jennifer A.
Muthupalani, Sureshkumar
Samson, Leona D
Date Issued
April 2016
Journal
Oncotarget
Publisher
Impact Journals/National Center for Biotechnology Information (U.S.)
Citation
Yu, Amy Marie, Jennifer A. Calvo, Suresh Muthupalani, and Leona D. Samson. “The Mbd4 DNA Glycosylase Protects Mice from Inflammation-Driven Colon Cancer and Tissue Injury.” Oncotarget (May 9, 2016). © 2016 Impact Journals, LLC
Version
Final published version
Abstract
Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4[superscript –/–] mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4[superscript –/–] mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4[superscript –/–] immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4[superscript –/–] mice transplanted with WT bone marrow. Mbd4[superscript –/–] mice with WT bone marrow behaved similarly to Mbd4[superscript –/–] mice. Together, our results indicate that the colonic epithelium of Mbd4[superscript –/–] mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Division of Comparative Medicine
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.18632/oncotarget.8721
