Magnesium, Essential for Base Excision Repair Enzymes, Inhibits Substrate Binding of N-Methylpurine-DNA Glycosylase

N-Methylpurine-DNA glycosylase (MPG) initiates base excision repair in DNA by removing a wide variety of alkylated, deaminated, and lipid peroxidation-induced purine adducts. MPG activity and other DNA glycosylases do not have an absolute requirement for a cofactor. In contrast, all downstream activities of major base excision repair proteins, such as apurinic/apyrimidinic endonuclease, DNA polymerase β, and ligases, require Mg2+. Here we have demonstrated that Mg2+ can be significantly inhibitory toward MPG activity depending on its concentration but independent of substrate type. The pre-steady-state kinetics suggests that Mg2+ at high but physiologic concentrations decreases the amount of active enzyme concentrations. Steady-state inhibition kinetics showed that Mg2+ affected Km, but not Vmax, and the inhibition could be reversed by EDTA but not by DNA. At low concentration, Mg2+ stimulated the enzyme activity only with hypoxanthine but not ethenoadenine. Real-time binding experiments using surface plasmon resonance spectroscopy showed that the pronounced inhibition of activity was due to inhibition in substrate binding. Nonetheless, the glycosidic bond cleavage step was not affected. These results altogether suggest that Mg2+ inhibits MPG activity by abrogating substrate binding. Because Mg2+ is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates. N-Methylpurine-DNA glycosylase (MPG) initiates base excision repair in DNA by removing a wide variety of alkylated, deaminated, and lipid peroxidation-induced purine adducts. MPG activity and other DNA glycosylases do not have an absolute requirement for a cofactor. In contrast, all downstream activities of major base excision repair proteins, such as apurinic/apyrimidinic endonuclease, DNA polymerase β, and ligases, require Mg2+. Here we have demonstrated that Mg2+ can be significantly inhibitory toward MPG activity depending on its concentration but independent of substrate type. The pre-steady-state kinetics suggests that Mg2+ at high but physiologic concentrations decreases the amount of active enzyme concentrations. Steady-state inhibition kinetics showed that Mg2+ affected Km, but not Vmax, and the inhibition could be reversed by EDTA but not by DNA. At low concentration, Mg2+ stimulated the enzyme activity only with hypoxanthine but not ethenoadenine. Real-time binding experiments using surface plasmon resonance spectroscopy showed that the pronounced inhibition of activity was due to inhibition in substrate binding. Nonetheless, the glycosidic bond cleavage step was not affected. These results altogether suggest that Mg2+ inhibits MPG activity by abrogating substrate binding. Because Mg2+ is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates. Cellular DNA is continuously exposed to endogenous or exogenous chemical or physical agents that induce DNA lesions. DNA base damage threatens genomic stability and cellular viability. Multiple DNA repair pathways exist in all organisms, from bacteria to humans, to preserve the integrity of the genome (1Lindahl T. Nature. 1993; 362: 709-715Crossref PubMed Scopus (4474) Google Scholar). If not repaired, damaged bases could be mutagenic (2Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D.C.1995: 59Google Scholar) and/or cause cell death by blocking DNA replication (3Larson K. Sharn J. Shenkar R. Strauss B. Mutat. Res. 1985; 233: 211-218Google Scholar). In all organisms, repair of DNA-containing small adducts, as well as altered and abnormal bases, occurs primarily via the base excision repair (BER) 2The abbreviations used are: BER, base excision repair; AP, apurinic/apyrimidinic; MPG, N-methylpurine-DNA glycosylase; APE, apurinic/apyrimidinic endonuclease; OGG, 8-oxoguanine-DNA glycosylase; Hx, hypoxanthine; ϵA, ethenoadenine; STO, single turnover. pathway, beginning with cleavage of the base by a DNA glycosylase (1Lindahl T. Nature. 1993; 362: 709-715Crossref PubMed Scopus (4474) Google Scholar, 2Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. American Society for Microbiology, Washington, D.C.1995: 59Google Scholar). Mechanistically, DNA glycosylases are categorized into two classes: mono- and bifunctional DNA glycosylases. Monofunctional DNA glycosylases, such as N-methylpurine-DNA glycosylase (MPG) and uracil-DNA glycosylase, use an activated water molecule as a nucleophile to generate an apurinic or apyrimidinic (AP) site in DNA. Bifunctional DNA glycosylases/AP lyases, such as NTH1 and OGG1, use an activated amino group (Lys) or imino group (Pro) as the nucleophile to create a Schiff base intermediate that coordinates base removal and subsequent strand incision (AP lyase) 3′ to the AP site (4Breimer L. Lindahl T. J. Biol. Chem. 1984; 259: 5543-5548Abstract Full Text PDF PubMed Google Scholar, 5Hatchet Z. Kow Y.W. Purmal A.A. Cunninghum R.R.P. Wallace S.S. J. Biol. Chem. 1994; 269: 18814-18820Abstract Full Text PDF PubMed Google Scholar). The mammalian MPG is known to excise at least 17 structurally diverse modified bases from DNA (6Singer B. Hang B. Chem. Res. Toxicol. 1997; 10: 713-732Crossref PubMed Scopus (127) Google Scholar). These lesions include 3-alkylpurines, 7-alkylguanine, 1,N6-ethenoadenine (ϵA), N2,3-ethenoguanine, and hypoxanthine (Hx), all of which are purine derivatives (7Roy R. Biswas T. Hazra T.K. Roy G. Grabowski D.T. Izumi T. Srinivasan G. Mitra S. Biochemistry. 1998; 37: 580-589Crossref PubMed Scopus (54) Google Scholar, 8Roy R. Brooks C. Mitra S. Biochemistry. 1994; 33: 15131-15140Crossref PubMed Scopus (51) Google Scholar, 9Roy R. Kennel S.J. Mitra S. Carcinogenesis. 1996; 17: 2177-2182Crossref PubMed Scopus (40) Google Scholar, 10O' Connor T.R. Nucleic Acids Res. 1993; 21: 5561-5569Crossref PubMed Scopus (136) Google Scholar, 11Saparbaev M. Laval J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 5873-5877Crossref PubMed Scopus (240) Google Scholar, 12Dosanjh M.K. Roy R. Mitra S. Singer B. Biochemistry. 1994; 33: 1624-1628Crossref PubMed Scopus (95) Google Scholar). Moreover, the base alterations are located in both the major and minor grooves of duplex DNA. Its orthologs in Escherichia coli (AlkA) and yeast (MAG) have an overlapping although not identical substrate range. Nonetheless mammalian MPG and E. coli AlkA do not share significant sequence similarity or structural homology (13Labahn J. Scharer O.D. Long A. Ezaz-Nikpay K. Verdine G.L. Ellenberger T.E. Cell. 1998; 86: 321-329Abstract Full Text Full Text PDF Scopus (232) Google Scholar, 14Lau A.Y. Scharer O.D. Samson L. Verdine G.L. Ellenberger T. Cell. 1998; 95: 133-157Abstract Full Text Full Text PDF Scopus (276) Google Scholar), despite this functional similarity and the fact that 3-methyladenine is a preferred substrate for both. MPG excises ϵA and Hx more efficiently than AlkA and MAG (11Saparbaev M. Laval J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 5873-5877Crossref PubMed Scopus (240) Google Scholar), but unlike AlkA, it cannot excise O2-alkylpyrimidines (15Lindahl T. Sedgwick B. Sekiguchi M. Nakabeppu Y. Annu. Rev. Biochem. 1988; 57: 133-157Crossref PubMed Scopus (626) Google Scholar, 16McCarthy T.V. Karran P. Lindahl T. EMBO J. 1984; 3: 545-550Crossref PubMed Scopus (211) Google Scholar) and oxidized bases such as 5-formyluracil and 5-hydroxymethyluracil (17Bjelland S. Birkeland N.K. Benneche T. Volden G. Seeberg E. J. Biol. Chem. 1994; 269: 30489-30495Abstract Full Text PDF PubMed Google Scholar) from DNA. MAG also does not excise O2-methylthymine (6Singer B. Hang B. Chem. Res. Toxicol. 1997; 10: 713-732Crossref PubMed Scopus (127) Google Scholar, 18Bjoras M. Klungland A. Johansen R.F. Seeberg E. Biochemistry. 1995; 34: 4577-4582Crossref PubMed Scopus (46) Google Scholar). The role of the magnesium (Mg2+) ion on DNA glycosylases is not well established. Notably, intranuclear Mg2+ concentration is highly variable. Depending on conditions, its may vary up to 75 mm. Unlike the normal cells, tumor cells have a higher Mg2+ content in the nucleus (19Kroeger H. Trosch W. J. Cell. Physiol. 1974; 83: 19-25Crossref PubMed Scopus (19) Google Scholar, 20Lukacs G.L. Zs-Nagy I. Steiber J. Gyori F. Balazs G. Scanning Microsc. 1996; 10: 1191-1200PubMed Google Scholar). It is reported that 5–10% of total Mg2+ is in a free state in the cells (21Li-Smerin Y. Levitan E.S. Johnson J.W. J. Physiol. 2001; 533: 729-743Crossref PubMed Scopus (43) Google Scholar). A recent report suggests that Mg2+ reduces the efficiency of the base excision and strand incision activities of hOGG1 on DNA containing 8-oxoG under single turnover conditions (22Morland I. Luna L. Gustad E. Seeberg E. Bjørås M. DNA Repair. 2005; 4: 381-387Crossref PubMed Scopus (40) Google Scholar); however, the reduction was more pronounced for the AP-lyase activity. The Schiff base formation between hOGG1- and 8-oxoG-containing DNA was abrogated in the presence of Mg2+. These results suggest that hOGG1 operates mainly as a monofunctional glycosylase under physiologic concentrations of Mg2+ (22Morland I. Luna L. Gustad E. Seeberg E. Bjørås M. DNA Repair. 2005; 4: 381-387Crossref PubMed Scopus (40) Google Scholar). There is a growing list of DNA glycosylases that cleave the damaged base depending on the base opposite to the damaged one. For example, for base discrimination, human endonuclease III (hNTH1) depends strongly on Mg2+ (23Eide L. Luna L. Gustad E. Henderson P.T. Essigmann J.M. Demple B. Seeberg E. Biochemistry. 2001; 40: 6653-6659Crossref PubMed Scopus (64) Google Scholar). However, Mg2+ has also been shown to stimulate the turnover of thymine-DNA glycosylase (24Waters T.R. Gallinari P. Jiricny J. Swann P.F. J. Biol. Chem. 1999; 274: 67-74Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Mg2+ acts as a cofactor of many enzymes involved in oxidative phosphorylation, nucleic acids and protein synthesis, and mitotic activity of normal cells. The adult human body contains 21–28 g of Mg2+. As a nutritional element the daily requirement of Mg2+ (200–700 mg) is crucial (25Bronzetti G. Croce C.D. Davini T. J. Environ. Pathol. Toxicol. Oncol. 1995; 14: 197-204PubMed Google Scholar). In the present study, we have demonstrated that Mg2+ is not required for MPG activity. However, Mg2+ can inhibit MPG activity significantly, at physiologically relevant concentrations, by abrogating its substrate binding ability without any effect on its catalytic chemistry. Because Mg2+ is an absolute requirement for the downstream activities of the major BER enzymes (26Izumi T. Wiederhold L.R. Roy G. Roy R. Jaiswal A. Bhakat K.K. Mitra S. Hazra T.K. Toxicology. 2003; Scopus Google Scholar), it may act as a regulator for the BER pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates. of MPG and the as R. Biswas T. Mitra S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). substrate containing Hx and ϵA, with the sequence ϵA or was from and The containing an A opposite ϵA or Hx was by the DNA at the of The on a The Hx or ϵA was at the using and and to a to a duplex as R. Biswas T. Mitra S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). MPG proteins, and with or duplex in the presence of duplex or in for at in an and in a total of The was by the enzyme at 75 for The containing the AP into by with a amount of AP at for the concentration of Mg2+ was to R. Biswas T. Mitra S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The was with of containing DNA from and and at for The by at using containing and in the was by the to and the using an with DNA of a of of MPG activity by we the binding using a A duplex containing an Hx or at the from the of strand was used for and on at concentrations and the surface plasmon resonance There is an to using the MPG the protein for binding the protein is less in the Hx cleavage with an inhibitory effect to Mg2+ not it was to the substrate binding with the The binding kinetics for containing Hx or was with a of MPG concentrations. The at protein concentrations to the binding on and protein concentrations. we the effect of concentration of Mg2+ on MPG binding toward Hx or enzymes with duplex at in an and in a total of of at and at in a we the Mg2+ effect at concentrations of The containing the AP into by on in the was also as for the activity enzymes with a duplex at under conditions to for the Steady-state enzyme was with a duplex for at under conditions to The also and as for the activity of Mg2+ and on MPG activity of MPG was in the presence of concentration using Hx as a Mg2+ showed a effect with Hx at concentrations, a higher concentration of Mg2+ MPG significantly A and Mg2+ the but an amount of EDTA could activity of MPG not have an effect on the However, as a a significantly higher for than for and the results in with on it that the inhibition of MPG is Mg2+ has been shown to the of DNA (26Izumi T. Wiederhold L.R. Roy G. Roy R. Jaiswal A. Bhakat K.K. Mitra S. Hazra T.K. Toxicology. 2003; Scopus Google Scholar). Mg2+ may the DNA and inhibit the binding of MPG to the DNA this by an amount of containing in of The results showed that unlike DNA could not MPG activity from the DNA concentration the activity of MPG inhibition of activity is for MPG and other DNA glycosylases (26Izumi T. Wiederhold L.R. Roy G. Roy R. Jaiswal A. Bhakat K.K. Mitra S. Hazra T.K. Toxicology. 2003; Scopus Google Scholar). it is that to Mg2+ MPG protein but not the substrate DNA. we the effect of other on and a pronounced inhibitory was the The for in MPG as Mg2+ Because MPG has substrate we DNA other than Hx for of the MPG activity and that Mg2+ could inhibit the MPG excision activity for However, was by Mg2+ in excision of ϵA by As EDTA MPG activity toward ϵA excision from Mg2+ inhibition not These results demonstrated that Mg2+ can be or significantly inhibitory toward MPG activity depending on its concentration and substrate of EDTA on MPG was with under conditions to for with the of the of and EDTA concentrations. with from independent of DNA on MPG was with under conditions to shown for with the of the of concentrations of duplex DNA of the sequence as the DNA. with from independent of product formation by in Hx cleavage of the ion required to inhibit of the MPG of the ion required to inhibit of the MPG activity. in a for of MPG by to be the the we the of Mg2+ inhibition Mg2+ is an absolute requirement for the of the downstream enzymes in the BER this we the major of the pre-steady-state kinetics to the of Mg2+ inhibition of MPG activity. the to the intermediate that be affected by Mg2+. the intermediate of the MPG In we and have showed that DNA glycosylases such as MPG and generate a in which an or occurs to cleave the glycosidic bond (7Roy R. Biswas T. Hazra T.K. Roy G. Grabowski D.T. Izumi T. Srinivasan G. Mitra S. Biochemistry. 1998; 37: 580-589Crossref PubMed Scopus (54) Google Scholar, Roy R. J. Biol. PubMed Scopus Google Scholar, S.S. Biochemistry. 1998; 37: PubMed Scopus Google Scholar, A.Y. Ellenberger T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the enzyme from the the AP and to a molecule of of the at are for MPG and in for all of the DNA glycosylases (7Roy R. Biswas T. Hazra T.K. Roy G. Grabowski D.T. Izumi T. Srinivasan G. Mitra S. Biochemistry. 1998; 37: 580-589Crossref PubMed Scopus (54) Google Scholar, Roy R. J. Biol. PubMed Scopus Google Scholar, S.S. Biochemistry. 1998; 37: PubMed Scopus Google Scholar, A.Y. Ellenberger T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the effect of Mg2+ on substrate binding using surface plasmon resonance in of the of MPG and the effect of Mg2+ on the glycosidic bond cleavage step by kinetics and the product step by turnover In the turnover conditions to the active enzyme concentration that be affected by Mg2+. to containing Hx was and on to a of resonance not with a sequence was used as a can with other used such as a the binding conditions for containing Hx or by MPG at The was and the resonance A and The at protein concentrations to the on and protein concentrations. that the for and and that MPG both the with higher for we the effect of Mg2+ on MPG binding toward and that Mg2+ the between MPG and Hx at a concentration and significantly the at its higher concentrations in a These results suggest that the of substrate binding by Mg2+ altered the activity of by the that Mg2+ can inhibit MPG, of substrate we Mg2+ any of the catalytic intermediate other than the binding kinetics with MPG to the Roy R. J. Biol. PubMed Scopus Google Scholar, S.S. Biochemistry. 1998; 37: PubMed Scopus Google Scholar, A.Y. Ellenberger T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The was at substrate and enzyme concentrations of and using the the of the and is the with the the conditions all of the substrate by The binding step not the of product and under conditions can be as concentrations of the was for that Mg2+ does not the step of MPG activity. we the of product and active enzyme concentration for the Roy R. J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The turnover of MPG excision of Hx the to under conditions of the substrate and enzyme concentration and The to the the the presence of state and the the which is the of enzyme the state of is to the of chemical at state under the required to the of product in and the of product formation in are the The the to pre-steady-state kinetics without using of product concentration using to the of the and of the In of the in and can be by the and is the for the pre-steady-state the product is from the that which and to and The the of the which is to the active enzyme concentration involved in the glycosylase we used of protein for all we that with Mg2+ concentration, active MPG concentration significantly The for product was from the was from the of the of the The for MPG is low and is in the turnover and product inhibition are the of of the DNA glycosylases R. Biswas T. Mitra S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, Mg2+ could significantly the active protein in the but it not any significant in product the of it that Mg2+ to the MPG its substrate DNA binding and its activity. of Mg2+ on Steady-state from pre-steady-state kinetics that Mg2+ inhibits MPG by we the inhibition by using of Mg2+ but not significantly the of substrate binding of MPG by of Mg2+ on of in a In the present study, we have demonstrated that Mg2+ can be or significantly inhibitory toward MPG activity depending on its concentration and substrate type. is a more than Mg2+. Moreover, the cell nucleus contains a of which MPG activity as however, from the BER it was to the of Mg2+ as Mg2+ is an absolute cofactor for not all of the downstream BER Unlike enzymes, MPG and other DNA glycosylases do not require Mg2+ or any other cofactor for damage and/or excision (26Izumi T. Wiederhold L.R. Roy G. Roy R. Jaiswal A. Bhakat K.K. Mitra S. Hazra T.K. Toxicology. 2003; Scopus Google Scholar). we Mg2+ as a of MPG to a and the concentration of Mg2+. The is required for activity for the incision and strand at AP which are base Mg2+ activity without on its glycosylase activity (22Morland I. Luna L. Gustad E. Seeberg E. Bjørås M. DNA Repair. 2005; 4: 381-387Crossref PubMed Scopus (40) Google Scholar). Here we that Mg2+ can inhibit the glycosylase activity of a monofunctional DNA glycosylase, Notably, or was shown to be by Mg2+ in a binding of from and also affected its activity 2001; 57: PubMed Scopus Google Scholar). The single in a A.Y. Samson Ellenberger T. Proc. Natl. Acad. Sci. U. S. A. Scopus Google Scholar). results that Mg2+ can inhibit the activity of MPG in a by abrogating its substrate binding. It could be by the structural integrity of the catalytic via an with in the and by However, it was not to the such as could inhibition of MPG Mg2+ of the MPG activity in the presence of which suggests an higher of MPG for Mg2+. high concentrations of are to Mg2+ in structural of MPG in the presence of Mg2+ are required to the of MPG It is that MPG in a cannot be in the presence of Mg2+. A.Y. Samson Ellenberger T. Proc. Natl. Acad. Sci. U. S. A. Scopus Google Scholar) could not Mg2+ in their although used high concentrations of Mg2+ the results showed that Mg2+ inhibits substrate which their showed that Mg2+ decreases active enzyme can that other than the may have an effect on MPG activity. have shown that MPG for activity. used the concentration in all for this that was present in the and that the of by an mm. this is with the of the MPG activity If the is crucial for MPG could a inhibitory all used in this the However, results that this was not the The not the MPG activity. also that Mg2+ at a low concentration a in MPG which could be due to a more of the substrate or to the protein A was with human endonuclease III enzyme (23Eide L. Luna L. Gustad E. Henderson P.T. Essigmann J.M. Demple B. Seeberg E. Biochemistry. 2001; 40: 6653-6659Crossref PubMed Scopus (64) Google Scholar). Because of MPG was only with Hx, not ϵA, it is to that DNA the damaged base or the than the MPG was affected by low Mg2+ to cause in activity. is the of an for the enzyme MPG, a DNA glycosylase, with and cleavage for a wide variety of structurally diverse alkylated, deaminated, and DNA adducts. the of DNA repair glycosylases in the of repair of mutagenic and toxic DNA base by endogenous and exogenous such as oxidative and replication and are not many well for this of BER glycosylase a has been shown to inhibit uracil-DNA glycosylase, which excises in DNA from replication J. Biol. Chem. Full Text PDF PubMed Google Scholar). E. J.M. M. Laval J. Z. B. 2005; PubMed Scopus Google Scholar) a of base and a mutagenic DNA in which a of E. coli and human DNA glycosylases. The was for E. coli protein and was shown to inhibit its excision activity inhibits DNA glycosylases such as AlkA, MPG, and by the DNA E. J.M. M. Laval J. Z. B. 2005; PubMed Scopus Google Scholar). In cellular at physiologically relevant concentrations, Mg2+ is not but is required to genomic In to its effect on DNA and Mg2+ is an cofactor in all involved in major of replication and enzyme inhibition is not For Mg2+ acts as a cofactor. as an cofactor in excision BER, and repair Mg2+ is required for the removal of DNA damage by endogenous and DNA Mg2+ concentrations are highly and Mg2+ acts as an regulator of cell and (25Bronzetti G. Croce C.D. Davini T. J. Environ. Pathol. Toxicol. Oncol. 1995; 14: 197-204PubMed Google Scholar). Mg2+ concentration in the nucleus (19Kroeger H. Trosch W. J. Cell. Physiol. 1974; 83: 19-25Crossref PubMed Scopus (19) Google Scholar). intranuclear concentrations of Mg2+ may in to DNA and its effect on repair pathways are to be The in of the in MPG activity with in Mg2+ concentration are not are not for in the amount of free Mg2+ in cells to MPG under of low Mg2+ concentration, efficient binding of damaged DNA substrate and cleavage to generate AP The effect of Mg2+ concentration to AP without cleavage and cells from the effect of AP AP are more mutagenic and toxic than any of the MPG In fact MPG could not cells it and of of AP and repair M. R. Samson J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Samson J. 1999; PubMed Google Scholar, Y. J. Nucleic Acids Res. 2005; 33: PubMed Scopus Google Scholar). to the and balanced under Mg2+ concentration MPG for of other BER enzymes such as DNA polymerase and The high inhibitory Mg2+ concentration of MPG also the inhibition of repair the and the in Mg2+ concentration act as for the BER pathway to efficient and balanced repair of base damage and genomic and such of Mg2+ BER in the cells in to DNA damage to be Izumi from S. for of and Biswas of for the also and for and

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