Ada regulon
In DNA repair, the Ada Regulon is a set of genes whose expression is essential to adaptive response (also known as "Ada response", hence the name), which is triggered in prokaryotic cells by exposure to sub-lethal doses of alkylating agents. This allows the cells to tolerate the effects of such agents, which are otherwise toxic and mutagenic.
The Ada response includes the expression of four genes: ada, alkA, alkB, and aidB. The product of ada gene, the Ada protein, is an activator of transcription of all four genes. DNA bases damaged by alkylation are removed by distinct strategies.
The alkylating agents from a group of mutagens and carcinogens that modify DNA by alkylation. Alkyl base lesions can arrest replication, interrupt transcription, or signal the activation of cell cycle checkpoints or apoptosis. In mammals, they could be involved in carcinogenesis, neurodegenerative disease and aging. The alkylating agents can introduce methyl or ethyl groups at all of the available nitrogen and oxygen atoms in DNA bases, providing a number of lesions.
The majority of evidence indicates that among the 11 identified base modification two, 3-methyladenine (3meA) and O6-methylguanine (O6-meG), are mainly responsible for the biological effects of alkylation agents.
The Ada protein is composed of two major domains, a C-terminal domain and an N-terminal one, linked by a hinge region susceptible to proteolytic cleavage. These domains can function independently. AdaCTD transfers methyl adducts from O6-meG and O4-meG onto its Cys-321 residue, whereas AdaNTD demethylates methyl-phosphotriesters by methyl transfer onto its Cys-38 residue.
The alkA gene encodes a glycosylase that repairs a variety of lesions including N-7-Methylguanine and N-3-Methylpurines and O2-methyl pyrimidines. The AlkA protein removes a damaged base from the sugar-phosphate backbone by cleaving the glycosylic bond attaching the base to the sugar, producing an abasic site. Further processing of the abasic site by AP endonucleases, polymerase I, and ligase then completes the repair.
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