Adaptive response

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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. [1] [2] It is initiated specifically 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, bacteria can adapt to the presence of the mutagen, rendering subsequent treatment with high doses of the same agent less effective. [3] [4]

Contents

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. [5] 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. [5] 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. [2]

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. [5] 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.[ citation needed ]

The E. coli Ada response

This response was first identified in E. coli. [6] The E. coli adaptive response constitutes of 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 covalently transfers methylation damage from DNA to one of its two active methyl acceptor cysteine residues: Cys38 and Cys321. [3] [7] 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. [3] It can also convert the protein from a weak to a strong activator of transcription, [8] increasing alkylation repair activity. [3]

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. [9]

alkB

alkB is an iron-dependent oxidoreductase, [10] 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. [5] 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. [5]

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

<span class="mw-page-title-main">Mutagen</span> Physical or chemical agent that increases the rate of genetic mutation

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 animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

<span class="mw-page-title-main">SOS response</span> Biological process

The SOS response is a global response to DNA damage in which the cell cycle is arrested and DNA repair and mutagenesis are induced. The system involves the RecA protein. The RecA protein, stimulated by single-stranded DNA, is involved in the inactivation of the repressor (LexA) of SOS response genes thereby inducing the response. It is an error-prone repair system that contributes significantly to DNA changes observed in a wide range of species.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

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 damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

<span class="mw-page-title-main">Base excision repair</span> DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

In molecular genetics, a regulon is a group of genes that are regulated as a unit, generally controlled by the same regulatory gene that expresses a protein acting as a repressor or activator. This terminology is generally, although not exclusively, used in reference to prokaryotes, whose genomes are often organized into operons; the genes contained within a regulon are usually organized into more than one operon at disparate locations on the chromosome. Applied to eukaryotes, the term refers to any group of non-contiguous genes controlled by the same regulatory gene.

Ada, also called as O6 alkyl guanine transferase I (O6 AGT I), is an enzyme induced by treatment of bacterial cells with alkylating agents that mainly cause methylation damage. This phenomenon is called the adaptive response hence the name. Ada transfers the alkyl group from DNA bases and sugar-phosphate backbone to a cysteine residue, inactivating itself. Consequently, it reacts stoichiometrically with its substrate rather than catalytically and is referred to as a suicide enzyme. Methylation of Ada protein converts it into a self transcriptional activator, inducing its own gene expression and the expression of other genes which together with Ada help the cells repair alkylation damage. Ada removes the alkyl group attached to DNA bases like guanine (O6-alkyl guanine) or thymine (O4-alkyl thymine) and to the oxygen of the phosphodiester backbone of the DNA. However, Ada shows greater preference for O6- alkyl guanine compared to either O4-thymine and alkylated phosphotriesters. Ada enzyme has two active sites, one for the alkylated guanines and thymines and the other for alkylated phosphotriesters.

AlkB (Alkylation B) is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage. AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by SN2 type of chemical agents. It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA. AlkB is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. It oxidatively demethylates the DNA substrate. Demethylation by AlkB is accompanied with release of CO2, succinate, and formaldehyde.

<span class="mw-page-title-main">Guanosine pentaphosphate</span> Chemical compound

(p)ppGpp, guanosine pentaphosphate and tetraphosphate, also known as the "magic spot" nucleotides, are alarmones involved in the stringent response in bacteria that cause the inhibition of RNA synthesis when there is a shortage of amino acids. This inhibition by (p)ppGpp decreases translation in the cell, conserving amino acids present. Furthermore, ppGpp and pppGpp cause the up-regulation of many other genes involved in stress response such as the genes for amino acid uptake and biosynthesis.

<span class="mw-page-title-main">Evelyn M. Witkin</span> American geneticist (1921–2023)

Evelyn M. Witkin was an American bacterial geneticist at Cold Spring Harbor Laboratory (1944–1955), SUNY Downstate Medical Center (1955–1971), and Rutgers University (1971–1991). Witkin was considered innovative and inspirational as a scientist, teacher and mentor.

In DNA repair, the Ada regulon is a set of genes whose expression is essential to adaptive response, 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.

<span class="mw-page-title-main">SOS chromotest</span>

The SOS chromotest is a biological assay to assess the genotoxic potential of chemical compounds. The test is a colorimetric assay which measures the expression of genes induced by genotoxic agents in Escherichia coli, by means of a fusion with the structural gene for β-galactosidase. The test is performed over a few hours in columns of a 96-well microplate with increasing concentrations of test samples. This test was developed as a practical complement or alternative to the traditional Ames test assay for genotoxicity, which involves growing bacteria on agar plates and comparing natural mutation rates to mutation rates of bacteria exposed to potentially mutagenic compounds or samples. The SOS chromotest is comparable in accuracy and sensitivity to established methods such as the Ames test and is a useful tool to screen genotoxic compounds, which could prove carcinogenic in humans, in order to single out chemicals for further in-depth analysis.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

DNA Polymerase V is a polymerase enzyme involved in DNA repair mechanisms in bacteria, such as Escherichia coli. It is composed of a UmuD' homodimer and a UmuC monomer, forming the UmuD'2C protein complex. It is part of the Y-family of DNA Polymerases, which are capable of performing DNA translesion synthesis (TLS). Translesion polymerases bypass DNA damage lesions during DNA replication - if a lesion is not repaired or bypassed the replication fork can stall and lead to cell death. However, Y polymerases have low sequence fidelity during replication. When the UmuC and UmuD' proteins were initially discovered in E. coli, they were thought to be agents that inhibit faithful DNA replication and caused DNA synthesis to have high mutation rates after exposure to UV-light. The polymerase function of Pol V was not discovered until the late 1990s when UmuC was successfully extracted, consequent experiments unequivocally proved UmuD'2C is a polymerase. This finding lead to the detection of many Pol V orthologs and the discovery of the Y-family of polymerases.

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

<span class="mw-page-title-main">Universal stress protein</span>

The universal stress protein (USP) domain is a superfamily of conserved genes which can be found in bacteria, archaea, fungi, protozoa and plants. Proteins containing the domain are induced by many environmental stressors such as nutrient starvation, drought, extreme temperatures, high salinity, and the presence of uncouplers, antibiotics and metals.

Ionizing radiation can cause biological effects which are passed on to offspring through the epigenome. The effects of radiation on cells has been found to be dependent on the dosage of the radiation, the location of the cell in regards to tissue, and whether the cell is a somatic or germ line cell. Generally, ionizing radiation appears to reduce methylation of DNA in cells.

<span class="mw-page-title-main">Alkb homolog 1, histone h2a dioxygenase</span> Protein-coding gene in the species Homo sapiens

AlkB homolog 1, histone H2A dioxygenase is a protein that in humans is encoded by the ALKBH1 gene.

References

  1. 1 2 3 4 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. 1 2 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. S2CID   1947211.
  3. 1 2 3 4 Volkert MR. (1988). Adaptive response of Escherichia coli to alkylation damage. Environ Mol Mutagen 11(2):241-55.
  4. ↑ Kamat, Aditya; Tran, Ngat T.; Sharda, Mohak; Sontakke, Neha; Le, Tung B. K.; Badrinarayanan, Anjana (2023-10-10), Widespread prevalence of a post-translational modification in activation of an essential bacterial DNA damage response, doi:10.1101/2023.10.09.561495 , retrieved 2024-02-28
  5. 1 2 3 4 5 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 . hdl: 10023/3327 .
  6. ↑ Samson, Leona; Cairns, John (May 1977). "A new pathway for DNA repair in Escherichia coli". Nature. 267 (5608): 281–283. doi:10.1038/267281a0. ISSN   1476-4687.
  7. ↑ He, Chuan; Hus, Jean-Christophe; Sun, Li Jing; Zhou, Pei; Norman, Derek P.G.; Dötsch, Volker; Wei, Hua; Gross, John D.; Lane, William S.; Wagner, Gerhard; Verdine, Gregory L. (October 2005). "A Methylation-Dependent Electrostatic Switch Controls DNA Repair and Transcriptional Activation by E. coli Ada". Molecular Cell. 20 (1): 117–129. doi: 10.1016/j.molcel.2005.08.013 .
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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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