title: The Mbd4 DNA glycosylase protects mice from inflammation-driven colon cancer and tissue injury.
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-/- mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4-/- mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4-/- mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4-/- immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4-/- mice transplanted with WT bone marrow. Mbd4-/- mice with WT bone marrow behaved similarly to Mbd4-/- mice. Together, our results indicate that the colonic epithelium of Mbd4-/- mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.
authors.forename: Amy Marie
authors.initials: AM
authors.lastname: Yu
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.|Biology Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.affiliation: Department of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.|Biology Department, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001397:Azoxymethane; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D047368:Tumor Burden / Q000235:genetics
chemical_list: D016264:Dextran Sulfate; D004706:Endodeoxyribonucleases; D045647:DNA Glycosylases; C492249:Mbd4 protein, mouse; D001397:Azoxymethane
keywords: AOM/DSS; Mbd4; colon cancer; inflammation; ulcerative colitis