Adaptive response

The adaptive response is a form of direct DNA repair in E. coli that protects DNA from damage by external agents or by errors during replication.[1] It is initiated against alkylation, particularly methylation, of guanine or thymine nucleotides or phosphate groups on the sugar-phosphate backbone of DNA. Under sustained exposure to low-level treatment with alkylating mutagens, E. coli can adapt to the presence of the mutagen, rendering subsequent treatment with high doses of the same agent less effective.[2] This mechanism has four related genes, also known as “SOS genes”: ada, alkA, alkB, and aidB, each one working in specific residues, all regulated by ada protein.

The adaptive response is mediated by the ada protein (a part of the ada regulon), which covalently transfers alkyl groups from the damaged DNA to one of its two active methyl acceptor cysteine residues: Cys69 and Cys321.[2] 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.[2] It can also convert the protein from a weak to a strong activator of transcription,[3] increasing alkylation repair activity.[2]

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.[4] 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[4]. 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. [5]

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.[4] 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.[2] 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.[2]

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.[1]

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.[1]

aidB

The aidB product is a flavin-containing protein.[6]

alkB

alkB is an iron-dependent oxidoreductase,[7] 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.[1]

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. A key experiment that reveals the underlying mechanisms is that which involves the treatment with protein synthesis inhibitors to Oedogonium Chlamydomonas and Closterium cells.[4] 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.[4]

gollark: It's a theorem prover. It can tell you if certain statements/sets of statements are satisfiable, and if so how.
gollark: And I don't think rust does TCO in general.
gollark: Halting is a side effect though.
gollark: Hmm, I wonder if I can horribly abuse z3 for collatz like I abused it for mazes.
gollark: But for applications where you know n < 2^64 you can just hardcode it yourself if you care.

References
  1. 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.
  2. Volkert MR. (1988). Adaptive response of Escherichia coli to alkylation damage. Environ Mol Mutagen 11(2):241-55.
  3. Sedgwick, B., Robins, P., Totty, Nick., Lindahl, Tomas.Functional Domains and Methyl Acceptor Sites of the Escherichia coli Ada Protein*. v. 263. n 9. p 4430-4433, 1998.
  4. Dimova EG, Bryant PE, Chankova SG (2008). "Adaptive response: some underlying mechanisms and open questions". Genetics and Molecular Biology. 31 (2): 396–408. doi:10.1590/S1415-47572008000300002.
  5. Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, et al. (July 2007). "Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework". Toxicology and Applied Pharmacology. 222 (1): 122–8. doi:10.1016/j.taap.2007.02.015. PMID 17459441.
  6. 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.
  7. 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.
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