DNA mismatch repair and DNA methylation in adult brain neurons

Abstract

DNA repair is essential for maintaining the integrity of the nucleotide sequence of cellular DNA over time. Although much information has accumulated recently on the mechanisms of DNA repair in cultured cells, little is known about the DNA repair capabilities of cells in the adult brain. In the present study, we have investigated the capacity of nuclear extracts from adult rodent brain neurons to carry out DNA mismatch repair. We focused on the repair of G.T and G.U mismatches, which are caused by deamination of 5-methyl cytosine to thymine, or cytosine to uracil, respectively, because these are the only types of mismatches that can arise in nondividing cells. We found that nuclear extracts from adult brain neurons can correct G.T and G.U mismatches, restoring them to G:C base pairs. Several other types of DNA mismatches could not be processed. These data provide the first direct demonstration that neurons in the adult mammalian brain have the capability to carry out DNA mismatch repair. We also we report that adult brain contains high levels of DNA methyltransferase (MTase) activity. We propose that one function of DNA MTase in the adult brain is to remethylate newly incorporated cytosine residues from G.T mismatch repair after deamination of 5-methyl cytosine, thereby maintaining the original pattern of DNA methylation. The high levels of brain DNA MTase suggest further that this enzyme has additional functions in the brain.