Molecular Mechanism of Adaptive Response to Alkylating Agents

  • Mutsuo Sekiguchi
  • Hidemasa Kondo
  • Kunihiko Sakumi
  • Yusaku Nakabeppu
Part of the Basic Life Sciences book series (BLSC, volume 39)


Alkylating agents are potent mutagens and carcinogens, and organisms respond in a complex manner to these agents. Growth of Escherichia coli in the presence of low levels of simple alkylating agents, such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), results in a marked increase in resistance of cells to both the mutagenic and the lethal effects of challenging doses of the same agents (24). This adaptive response is distinct from previously characterized pathways of DNA repair, particularly from the SOS response, another inducible effect resulting from DNA damage. The adaptation does not lead to expression of the SOS functions, and recA and lexA mutant cells that are unable to perform SOS repair can be adapted to MNNG (8, 27).


Adaptive Response Alkylating Agent Transcription Initiation Site alkB Gene alkA Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Clarke, N.D., M. Kvaal, and E. Seeberg (1984) Cloning of Escherichia coli genes encoding 3-methyladenine DNA glycosylase I and II. Molec. Gen. Genet. 197:368–372.CrossRefGoogle Scholar
  2. 2.
    Demple, B., A. Jacobsson, M. Olsson, P. Robins, and T. Lindahl (1982) Repair of alkylated DNA in Escherichia coli: Physical properties of -methylguanine-DNA methyltransferase. J. Biol. Chem. 257:13776–13780.Google Scholar
  3. 3.
    Demple, B., B. Sedgwick, P. Robins, N. Totty, M.D. Waterfield, and T. Lindahl (1985) Active site and complete sequence of the suicidal meth- yltransferase that counters alkylation mutagenesis. Proc. Natl. Acad. Sei., USA 82:2688–2692.CrossRefGoogle Scholar
  4. 4.
    Evensen, G., and E. Seeberg (1982) Adaptation to alkylation resistance involves the induction of a DNA glycosylase. Nature (London) 296:773–775.CrossRefGoogle Scholar
  5. 5.
    Foote, R.S., S. Mitra, and B.C. Pal (1980) Demethylation of -methyl- guanine in synthetic DNA polymer by an inducible activity in Eschertichia coli. Biochem. Biophys. Res. Commun. 97:654–659CrossRefGoogle Scholar
  6. 6.
    Hawley, D.K., and W.R. McClure (1983) Compilation and analysis of Escherichia coli promoter DNA sequences. Nucl. Acids Res. 11:2237–2255.CrossRefGoogle Scholar
  7. 7.
    Jeggo, P. (1979) Isolation and characterization of Escherichia coli K-12 mutants unable to induce the adaptive response to simple alkylating agents. J. Bacteriol. 139:783–791.Google Scholar
  8. 8.
    Jeggo, P., M. Defais, L. Samson, and P. Schendel (1977) An adaptive response of E. coli to low levels of alkylating agent: Comparison with previously characterized DNA repair pathways. Molec. Gen. Genet. 157:1–9.CrossRefGoogle Scholar
  9. 9.
    Karran, P., T. Hjelmgren, and T. Lindahl (1982) Induction of a DNA glycosylase for N-methylated purines is part of the adaptive response to alkylating agents. Nature (London) 296:770–773.CrossRefGoogle Scholar
  10. 10.
    Karran, P., T. Lindahl, I. Ofsteng, G.B. Evensen, and E. Seeberg (1980) Escherichia coli mutants deficient in 3-methyladenine DNA glycosylase. J. Molec. Biol. 140:101–127.CrossRefGoogle Scholar
  11. 11.
    Kataoka, H., and M. Sekiguchi (1985) Molecular cloning and characterization of the alkB gene of Escherichia coli. Molec. Gen. Genet. 198: 263–269.Google Scholar
  12. 12.
    Kataoka, H., Y. Yamarooto, and M. Sekiguchi (1983) A new gene (alkB) of Escherichia coli that controls sensitivity to methylmethane sulfonate. J. Bacteriol. 153:1301–1307.Google Scholar
  13. 13.
    Lemotte, P.K., and G.C. Walker (1985) Induction and autoregulation of ada, a positively acting element regulating the response of Escherichia coli K-12 to methylating agents. J. Bacteriol. 161:888–895.Google Scholar
  14. 14.
    llargispn, G.P., D.P. Cooper, and J. Brennand (1985) Cloning of the E. coli -methylguanine and methylphosphotriester methyltransferase gene using a functional DNA repair assay. Nucl. Acids Res. 13:1939–1952.CrossRefGoogle Scholar
  15. 15.
    Mitra, S., B.C. Pal, and R.S. Foote (1982) -methylguanine-DNA meth- yltransf erase in wild-type and ada mutants of Escherichia coli. J. Bacteriol. 152:534–537.Google Scholar
  16. 16.
    Nakabeppu, Y., H. Kondo, S. Kawabata, S. Iwanaga, and M. Sekiguchi (1985) Purification and strCture of the intact Ada regulatory protein of Escherichia coli Kl 2, -methylguanine-DNA me thy Itransf erase. J. Biol. Chem. 260:7281–7288.Google Scholar
  17. 17.
    Nakabeppu, Y., H. Kondo, and M. Sekiguchi (1984) Cloning and charac-terization of the alkA gene of Escherichia coli that encodes 3-methyl- adenine DNA glycosylase II. J. Biol. Chem. 259:13723–13729.Google Scholar
  18. 18.
    Nakabeppu, Y., Y. Mine, and M. Sekiguchi (1985) Regulation of expression of the cloned ada gene in Escherichia coli. Mutat. Res. 146:155–167.Google Scholar
  19. 19.
    Nakabeppu, Y., T. Miyata, H. Kondo, S. Iwanaga, and M. Sekiguchi (1984) Structure and expression of the alkA gene of Escherichia coli involved in adaptive response to alkylating agents. J. Biol. Chem. 259:13730–13736.Google Scholar
  20. 20.
    Olsson, M., and T. Lindahl (1980) Repair f alkylated DNA in Escherichia coli: Methyl group transfer from -methylguanine to a protein cysteine residue. J. Biol. Chem. 255:10569–10571.Google Scholar
  21. 21.
    Pribnow, D. (1975) Nucleotide sequence of an RNA polymerase binding site at an early T7 promoter. Proc. Natl. Acad. Sei., USA 72:784–788.CrossRefGoogle Scholar
  22. 22.
    Riazuddin, S., and T. Lindahl (1978) Properties of 3-methyladenine-DNA glycosylase from Escherichia coli. Biochemistry 17:2110–2118.CrossRefGoogle Scholar
  23. 23.
    Rosenberg, M., and D. Court (1979) Regulatory sequences involved in the promotion and termination of RNA transcription. Ann. Rev. Genet. 13:319–353.CrossRefGoogle Scholar
  24. 24.
    Samson, L., and J. Cairns (1977) A new pathway for DNA repair in Es-cherichia coli. Nature (London) 267:281–283.CrossRefGoogle Scholar
  25. 25.
    Sedgwick, B. (1983) Molecular cloning of a gene which regulates the adaptive response to alkylating agents in Escherichia coli. Molec. Gen. Genet. 191:466–472.CrossRefGoogle Scholar
  26. 26.
    Sedgwick, B., and P. Robins (1980) Isolation of mutants of Escherichia coli with increased resistance to alkylating agents: Mutants deficient in thiols and mutants constitutive for the adaptive response. Molec. Gen. Genet. 180:85–90.CrossRefGoogle Scholar
  27. 27.
    Schendel, P.F., M. Defais, P. Jeggo, L. Samson, and J. Cairns (1978) Pathway of mutagenesis and repair in Escherichia coli exposed to low levels of simple alkylating agents. J. Bacteriol. 135:466–475.Google Scholar
  28. 28.
    Shine, J., and L. Dalgarno (1975) Determinant of cistron specificity in bacterial ribosomes. Nature (London) 254:34–38.CrossRefGoogle Scholar
  29. 29.
    Teo, I., B. Sedgwick, B. Demple, B. Li, and T. Lindahl (1984) Induction of resistance to alkylating agents in E. coli: The ada gene product serves both as a regulatory protein and as an enzyme for repair of mutagenic damage. EMBO J. 3:2151–2157.Google Scholar
  30. 30.
    Thomas, L., C.-H. Yang, and D.A. Goldthwait (1982) Two DNA glycosyl- ases in Escherichia coli which release primarily 3-methyladenine. Biochemistry 21:1162–1169.CrossRefGoogle Scholar
  31. 31.
    Yamamoto, Y., H. Kataoka, Y. Nakabeppu, T. Tsuzuki, and M. Sekiguchi (1983) The genes involved in the repair of alkylated DNA in Escherichia coli K-12. In Celluar Responses to DNA Damage, E.G. Friedberg and B.A. Bridges, eds. Alan R. Liss, Inc., New York, pp. 271–278.Google Scholar
  32. 32.
    Yamamoto, Y., M. Katsuki, M. Sekiguchi, and N. Otsuji (1978) Escherichia coli gene that controls sensitivity to alkylating agents. J. Biriol. 135:144–152.Google Scholar
  33. 33.
    Yamamoto, Y., and M. Sekiguchi (1979) Pathways for repair of DNA damaged by alkylating agent in Escherichia coli. Molec. Gen. Genet. 171: 251–256.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Mutsuo Sekiguchi
    • 1
    • 2
  • Hidemasa Kondo
    • 1
    • 2
  • Kunihiko Sakumi
    • 1
    • 2
  • Yusaku Nakabeppu
    • 1
    • 2
  1. 1.Department of Biology, Faculty of ScienceKyushu University 33Fukuoka 812Japan
  2. 2.Department of Biochemistry, Faculty of MedicineKyushu University 33Fukuoka 812Japan

Personalised recommendations