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.

Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer

“…In LUAD2, private mutations dominated by a signature for deamination of 5-mC (Fig. 6 ) were associated with germline variants in two genes functionally implicated in the repair of these mutations, MDB4 [ 25 ] and RPA1 [ 26 ] (Fig. 6 ; Supplementary Table S3 ).…”

Base excision repair causes age-dependent accumulation of single-stranded DNA breaks that contribute to Parkinson disease pathology

“…Recent studies of the pathways involved in AAG-induced retinal degeneration revealed potentially translatable therapeutic approaches (Allocca et al, 2019). Similarly, it has been reported that ischemic injury is less severe (Ebrahimkhani et al, 2014), and inflammation can be reduced (Yu et al, 2016) in DNA glycosylase-deficient cells. The data presented here demonstrate improved survival of DA neurons in old PD nematodes in the absence of exposure to DNA-damaging agents.…”

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“…Second, studies from the Samson laboratory have demonstrated that DNA damage from inflammation drives mutations as well as cancer development (23,359). In one such study, mice lacking the BER glycosylase Aag were treated with a common colitis model of DSS in drinking water.…”