The adaptive response is a DNA damage response pathway prevalent across bacteria that protects DNA from damage by external agents or by errors during replication.Landini, P, Volkert MR. (2000
Regulatory Responses of the Adaptive Response to Alkylation Damage: a Simple Regulon with Complex Regulatory Features
''J. Bacteriol.'' 182(23): 6543–6549. It is initiated specifically against

alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...

, particularly

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

, of

guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

thymine Thymine () (symbol T or Thy) is one of the four nucleotide bases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine ...

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

s or

phosphate Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthop ...

groups on the sugar-phosphate backbone of

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

. Under sustained exposure to low-level treatment with alkylating

mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

s, bacteria can adapt to the presence of the mutagen, rendering subsequent treatment with high doses of the same agent less effective.Volkert MR. (1988)
Adaptive response of ''Escherichia coli'' to alkylation damage.
''Environ Mol Mutagen'' 11(2):241-55.

Function

Environmental influence plays a crucial role in the developmental plasticity of genotypes due to the introduction of DNA damaging agents. This phenomenon and the defense mechanism that has evolved to protect an organism’s genotype against damage and prevent multiple phenotypes is known as the adaptive response. Since the adaptive response is able to prevent the possibility of different phenotypes it, therefore, allows organisms to minimize the stress effects it experiences from different stressors and eventually develop a resistance to the stressors. The effects of various chemical, biological, and physical genotoxic damaging agents jeopardize the genotypic integrity of all organisms; however, many evolutionary defense mechanisms have developed so that the stressors stimulate the adaptive response to reduce the stress to a more reasonable and manageable level and reduce genetic damage. Many of these defense mechanisms have contributed to the nonspecific adaptive response by "conditioning" the effected organisms with small amounts of particular stressors to stimulate cellular conformation changes and increase the resistance when the organism is exposed to higher concentrations of that particular stressor. For example, the decomposition of water produces highly reactive hydroxyl free radicals that can damage DNA, therefore, stimulating

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

mechanisms. This DNA up-regulation is involved in the adaptive response because the organism is being conditioned to protect itself against these stressors. Reactive oxygen species (ROS) are very damaging to DNA and highly associated with the adaptive response. When free radicals attack the important biomolecules that makeup organisms, harmful molecular intermediates react with and damage DNA leading to base damage or breaks in the dsDNA strand. The adaptive response is helpful to prevent damage and maintain the integrity of the genome.

The E. coli Ada response

This response was first identified in ''E. coli''. The ''E. coli'' adaptive response constitutes four genes: ''ada'', ''alkA'', '' alkB'', and '' aidB'', each one working in specific residues, all regulated by the ''E. coli'' Ada protein. The ''E. coli'' adaptive response is mediated by the Ada protein, which

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

ly transfers methylation damage from DNA to one of its two active methyl acceptor

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues: Cys38 and Cys321. The Ada protein can repair damage by transferring methyl groups from O6-methylguanine or O4-methylthymine to Cys321 and also from methylphosphotriesters to Cys38 residue through an irreversible process. It can also convert the protein from a weak to a strong activator of transcription,Sedgwick, B., Robins, P., Totty, Nick., Lindahl, Toma
Functional Domains and Methyl Acceptor Sites of the ''Escherichia coli'' Ada Protein*.
v. 263. n 9. p 4430-4433, 1998. increasing alkylation repair activity.

Ada

The ada gene has regulatory and repair activities, both really close to each other. For the regulation to occur, the ada protein must be activated, which is a consequence of the DNA repair activity.

alkA

The alkA gene product is a glycosylase that can repair a variety of lesions, removing a base from the sugar-phosphate backbone, producing an abasic site.

aidB

The aidB product is a flavin-containing protein.Rohankhedkar MS, Mulrooney SB, Wedemeyer WJ, Hausinger RP. (2006)
The AidB component of the ''Escherichia coli'' adaptive response to alkylating agents is a flavin-containing, DNA-binding protein.
''J Bacteriol'' 188(1):223-30.

alkB

alkB is an

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

-dependent

oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...

,Yu B, Edstrom WC, Benach J, Hamuro Y, Weber PC, Gibney BR, Hunt JF. (2006)
Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.
''Nature'' 439(7078):879-84. and it is associated with DNA repair because this gene is able to repair lesions in phage DNA prior to infection. It has been also demonstrated that alkB is required for reactivation of MMS-treated (methylating agent methyl methanesulfonate) single-stranded phage and since there are no lesions to be removed, it has been suggested that alkBB is involved in replication of damaged template DNA. Also, the fact that alkB can confer resistance to a methylating agent it suggests that it functions by itself.

Mechanism

Although little is known about the mechanism of the adaptive response, it is believed that changes in gene transcription and the activation of cellular defenses are involved. It has recently been suggested that specific mechanistic pathways of the adaptive response can activate the important tumor suppressor protein

p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

. A key experiment that reveals the underlying mechanisms is that which involves the treatment with protein synthesis inhibitors to Oedogonium Chlamydomonas and Closterium cells. This experiment resulted in DNA-binding proteins being synthesized in the cells conditioned with the stressor. Furthermore, reverse adaptive response suggests that a high conditioning dose followed by a second low dose produces roughly the same magnitude of response. This could suggest that the mechanisms work by cellular response modulation, not prevention, to the impending damage. The adaptive response is not instantaneous and takes several hours to develop, however after development it can last for months given that the stressor exposure is limited and will not overwhelm the cell. This is known as being dose and time-dependent with a maximum response occurring at 4 hours after an initial conditioning dose of 100 cGy (centigray) radiation stressor.

References

{{Reflist DNA repair Gene expression