{{Short description|Bacterial DNA damage response pathway}} The '''adaptive response to methylation damage''' (or the Ada response) is a bacterial DNA damage response pathway induced specifically upon exposure to DNA methylation damage.<ref>{{cite journal |last1=Landini |first1=Paolo |last2=Volkert |first2=Michael R. |title=Regulatory Responses of the Adaptive Response to Alkylation Damage: a Simple Regulon with Complex Regulatory Features |journal=Journal of Bacteriology |date=December 2000 |volume=182 |issue=23 |pages=6543–6549 |doi=10.1128/jb.182.23.6543-6549.2000 |pmid=11073893 |pmc=111391 }}</ref> It is initiated independently of the SOS response. Bacteria such as ''Escherichia coli'' exposed to sub-lethal doses of methylation damage activate the Ada response pathway. This enables their survival to subsequent exposure to high doses of the same agent (which are otherwise lethal).<ref name="Volkert">Volkert MR. (1988). [https://www.ncbi.nlm.nih.gov/pubmed/3278898 Adaptive response of ''Escherichia coli'' to alkylation damage.] ''Environ Mol Mutagen'' 11(2):241-55.</ref><ref>{{cite bioRxiv |last1=Kamat |first1=Aditya |title=Widespread prevalence of a post-translational modification in activation of an essential bacterial DNA damage response |date=2023-10-10 |language=en |biorxiv=10.1101/2023.10.09.561495 |last2=Tran |first2=Ngat T. |last3=Sharda |first3=Mohak |last4=Sontakke |first4=Neha |last5=Le |first5=Tung B. K. |last6=Badrinarayanan |first6=Anjana}}</ref> The Ada response was first identified in ''E. coli''; however, over the years diverse and widespread Ada response pathways have been identified across bacteria.<ref>{{cite journal |last1=Kamat |first1=Aditya |last2=Badrinarayanan |first2=Anjana |title=SOS-independent bacterial DNA damage responses: diverse mechanisms, unifying function |journal=Current Opinion in Microbiology |date=1 June 2023 |volume=73 |article-number=102323 |doi=10.1016/j.mib.2023.102323 |pmid=37148591 |pmc=7617703 }}</ref> The pathways typically vary in the domain organization of the regulatory protein that orchestrates the Ada response. <!-- citation for the specific cysteines? just don't want to get it backwards --->== 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.<ref name="Dimova_2008" /> 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.<ref name="Dimova_2008" /> 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.<ref name=":0">{{cite journal | vauthors = Calabrese EJ, Bachmann KA, Bailer AJ, Bolger PM, Borak J, Cai L, Cedergreen N, Cherian MG, Chiueh CC, Clarkson TW, Cook RR, Diamond DM, Doolittle DJ, Dorato MA, Duke SO, Feinendegen L, Gardner DE, Hart RW, Hastings KL, Hayes AW, Hoffmann GR, Ives JA, Jaworowski Z, Johnson TE, Jonas WB, Kaminski NE, Keller JG, Klaunig JE, Knudsen TB, Kozumbo WJ, Lettieri T, Liu SZ, Maisseu A, Maynard KI, Masoro EJ, McClellan RO, Mehendale HM, Mothersill C, Newlin DB, Nigg HN, Oehme FW, Phalen RF, Philbert MA, Rattan SI, Riviere JE, Rodricks J, Sapolsky RM, Scott BR, Seymour C, Sinclair DA, Smith-Sonneborn J, Snow ET, Spear L, Stevenson DE, Thomas Y, Tubiana M, Williams GM, Mattson MP | display-authors = 6 | title = Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework | journal = Toxicology and Applied Pharmacology | volume = 222 | issue = 1 | pages = 122–8 | date = July 2007 | pmid = 17459441 | doi = 10.1016/j.taap.2007.02.015 | bibcode = 2007ToxAP.222..122C | s2cid = 1947211 | url = https://escholarship.org/uc/item/4q35r8nb }}</ref>
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.<ref name="Dimova_2008" /> 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|date=May 2020}}
== The E. coli Ada response ==
This response was first identified in ''E. coli''.<ref>{{Cite journal |last1=Samson |first1=Leona |last2=Cairns |first2=John |date=May 1977 |title=A new pathway for DNA repair in Escherichia coli |url=https://www.nature.com/articles/267281a0 |journal=Nature |language=en |volume=267 |issue=5608 |pages=281–283 |doi=10.1038/267281a0 |pmid=325420 |bibcode=1977Natur.267..281S |issn=1476-4687|url-access=subscription }}</ref> 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 covalently transfers methylation damage from DNA to one of its two active methyl acceptor cysteine residues: Cys38 and Cys321.<ref name="Volkert" /><ref>{{Cite journal |last1=He |first1=Chuan |last2=Hus |first2=Jean-Christophe |last3=Sun |first3=Li Jing |last4=Zhou |first4=Pei |last5=Norman |first5=Derek P.G. |last6=Dötsch |first6=Volker |last7=Wei |first7=Hua |last8=Gross |first8=John D. |last9=Lane |first9=William S. |last10=Wagner |first10=Gerhard |last11=Verdine |first11=Gregory L. |date=October 2005 |title=A Methylation-Dependent Electrostatic Switch Controls DNA Repair and Transcriptional Activation by E. coli Ada |journal=Molecular Cell |language=en |volume=20 |issue=1 |pages=117–129 |doi=10.1016/j.molcel.2005.08.013|doi-access=free |pmid=16209950 }}</ref> 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.<ref name="Volkert" /> It can also convert the protein from a weak to a strong activator of transcription,<ref>Sedgwick, B., Robins, P., Totty, Nick., Lindahl, Tomas.[https://www.ncbi.nlm.nih.gov/pubmed/3162236 Functional Domains and Methyl Acceptor Sites of the ''Escherichia coli'' Ada Protein*.] v. 263. n 9. p 4430-4433, 1998.</ref> increasing alkylation repair activity.<ref name="Volkert" />
=== 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.<ref name="ncbi.nlm.nih.gov">Landini, P, Volkert MR. (2000) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC111391/ Regulatory Responses of the Adaptive Response to Alkylation Damage: a Simple Regulon with Complex Regulatory Features] ''J. Bacteriol.'' 182(23): 6543–6549.</ref>
=== 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.<ref name="ncbi.nlm.nih.gov" />
=== aidB ===
The aidB product is a flavin-containing protein.<ref name="Rohankhedar">Rohankhedkar MS, Mulrooney SB, Wedemeyer WJ, Hausinger RP. (2006). [http://jb.asm.org/content/188/1/223.full 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.</ref>
=== alkB ===
alkB is an iron-dependent oxidoreductase,<ref name="Yu">Yu B, Edstrom WC, Benach J, Hamuro Y, Weber PC, Gibney BR, Hunt JF. (2006). [https://www.ncbi.nlm.nih.gov/pubmed/16482161 Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.] ''Nature'' 439(7078):879-84.</ref> 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.<ref name="ncbi.nlm.nih.gov" />
== 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. A key experiment that reveals the underlying mechanisms is that which involves the treatment with protein synthesis inhibitors to Oedogonium Chlamydomonas and Closterium cells.<ref name="Dimova_2008">{{cite journal| vauthors = Dimova EG, Bryant PE, Chankova SG |date= 2008|title=Adaptive response: some underlying mechanisms and open questions |journal=Genetics and Molecular Biology|language=en|volume=31|issue=2|pages=396–408|doi=10.1590/S1415-47572008000300002|doi-access=free|hdl=10023/3327|hdl-access=free}}</ref> 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.<ref name="Dimova_2008" />
== References == {{Reflist}}
Category:DNA repair Category:Gene expression