A combination of direct reversion and nucleotide excision repair counters the mutagenic effects of DNA carboxymethylation

Abstract

Distinct cellular DNA damage repair pathways maintain the structural integrity of DNA and protect it from the mutagenic effects of genotoxic exposures and processes. The occurrence of O6-carboxymethylguanine (O6-CMG) has been linked to meat consumption and hypothesized to contribute to the development of colorectal cancer. However, the cellular fate of O6-CMG is poorly characterized and there is contradictory data in the literature as to how repair pathways may protect cells from O6-CMG mutagenicity. To better address how cells detect and remove O6-CMG, we evaluated the role of two DNA repair pathways in counteracting the accumulation and toxic effects of O6-CMG. We found that cells deficient in either the direct repair protein O6-methylguanine-DNA methyltransferase (MGMT), or key components of the nucleotide excision repair (NER) pathway, accumulate higher levels O6-CMG DNA adducts than wild type cells. Furthermore, repair-deficient cells were more sensitive to carboxymethylating agents and displayed an increased mutation rate. These findings suggest that a combination of direct repair and NER circumvent the effects O6-CMG DNA damage.