J. Biol. Chem., Vol. 263, Issue 27, 13490-13492, 09, 1988
Activation of Ada protein as a transcriptional regulator by direct alkylation with methylating agents
K Takahashi, Y Kawazoe, K Sakumi, Y Nakabeppu and M Sekiguchi
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
The adaptive response is a cellular process to induce DNA repair enzymes in
response to a challenge of alkylating agents. In this process Ada protein,
the product of the ada gene, plays a major role; it accepts the methyl
groups of the methylated DNA at the cysteine residues of its own molecule,
and the methylated form of Ada protein promotes transcription of its own
gene, thereby triggering induction of the whole process. In addition to
this DNA-mediated activation of Ada protein, we have proposed an
alternative mechanism which involves direct methylation of Ada protein by
methylating agents (Takahashi, K., and Kawazoe, Y. (1987) Biochem. Biophys.
Res. Commun. 144, 447-453). Here we present evidence that Ada protein is
activated as a transcriptional regulator through a direct methylation by
certain methylating agents. A purified preparation of Ada protein was
treated with various methylating agents, and the activity to promote
transcription of the ada gene was determined using an in vitro
reconstituted system. The ada-specific RNA was produced when the Ada
protein treated with methyl methanesulfonate or with methyl iodide was
present in the reaction mixture. The Ada protein treated with N-methyl-
N-nitrosourea did not show such an activity. It is, therefore, suggested
that the adaptive response induced by chemoselective methylating agents
such as methyl iodide might be due, at least in part, to the direct
methylation of the constitutive Ada protein present in the cell.
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