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The adaptive response is a form of direct
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
in '' E. coli'' 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 against
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. 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 effectin ...
, particularly
methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
, of
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases 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 is ...
or
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases 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 pyrimidin ...
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
s or
phosphate 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 orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...
groups on the sugar-phosphate backbone of DNA. Under sustained exposure to low-level treatment with
alkylating Alkylation is the transfer of an alkyl group from one molecule to another. 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 effectin ...
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 i ...
s, ''E. coli'' 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.
This mechanism has four related genes, also known as “SOS genes”:
ada Ada may refer to: Places Africa * Ada Foah, a town in Ghana * Ada (Ghana parliament constituency) * Ada, Osun, a town in Nigeria Asia * Ada, Urmia, a village in West Azerbaijan Province, Iran * Ada, Karaman, a village in Karaman Province, T ...
, alkA,
alkB AlkB (Alkylation B) is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage.Errol C.Friedberg, Graham c. Walker, Wolfram Siede, Richard D. Wood, Roger A. schultz, Tom Ellenberge ...
, and aidB, each one working in specific residues, all regulated by
ada Ada may refer to: Places Africa * Ada Foah, a town in Ghana * Ada (Ghana parliament constituency) * Ada, Osun, a town in Nigeria Asia * Ada, Urmia, a village in West Azerbaijan Province, Iran * Ada, Karaman, a village in Karaman Province, T ...
protein. The adaptive response is mediated by the ada protein (a part of the ada regulon), 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 alkyl groups from the damaged DNA to one of its two active methyl acceptor
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...
residues: Cys69 and Cys321. Ada protein can repair the damage by transferring methyl groups from O6-methylguanine or O4-methylthymine to Cys321 and also from methylphosphotriesters to Cys69 residue through an irreversible process. It can also convert the protein from a weak to a strong activator of transcription, increasing alkylation repair activity.


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 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.


SOS genes

Four SOS genes have been identified that contribute to the adaptive response against methylating agents: ada, alkA, alkB and aidB. ada and alkB are cotranscribed from a single promoter. That said, they constitute an
operon In genetics, an operon is a functioning unit of DNA containing a cluster of genes under the control of a single promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo splic ...
. The SOS genes share a common regulatory mechanism and constitutes a general defense against DNA damage. Cells that have deficiency in one or more SOS genes tend to have a slower response, leading to a higher DNA damage through ultraviolet radiation and others agents.


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 In biochemistry and molecular genetics, an AP site (apurinic/apyrimidinic site), also known as an abasic site, is a location in DNA (also in RNA but much less likely) that has neither a purine nor a pyrimidine base, either spontaneously or du ...
.


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 with symbol Fe (from la, ferrum) 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, right in ...
-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 ...
,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 active 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 protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
. 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