Transcription factors NF-YA regulate the induction of human OGG1 following DNA-alkylating agent methylmethane sulfonate (MMS) treatment

A human 8-oxoguanine- DNA glycosylase (hOGG1) is the main enzyme that repairs 8-oxoG, which is a critical mutagenic lesion. There is a great deal of interest in the up- or down-regulation of OGG1 expression after DNA damage. In this study, we investigated the effect of a DNA-alkylating agent, methylmethane sulfonate (MMS), on hOGG1 expression level and found that MMS treatment resulted in an increase in the functional hOGG1 expression in HCT116 cells. A region between -121 and -61 of the hOGG1 promoter was found to be crucial for this induction by MMS. Site-directed mutations of the two inverted CCAAT motifs substantially abrogated the induction of the hOGG1 promoter as a result of MMS treatment. In addition, the NF-YA protein ( binding to the inverted CCAAT box) was induced after exposing cells to MMS. Moreover, gel shift and supershift analyses with the nuclear extracts prepared from HCT116 cells identified NF-YA as the transcription factor interacting with the inverted CCAAT box. Mutations of the inverted CCAAT box either prevented the binding of this factor or abolished its activation as a result of MMS treatment. Finally, this study showed that hOGG1-expressing HCT116 cells exhibited increased hOGG1 repair activity and resistance to MMS. Overall, these results demonstrate that MMS can up- regulate hOGG1 expression through the induction of the transcription factor, NFYA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS.