Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Recent progress on the Ada response for inducible repair of DNA alkylation damage

Oncogene volume 21, pages 8886–8894 (2002)Cite this article

Methylating agents comprise a major class of DNA damaging compounds that occur both endogenously and in the environment. They are extremely cytotoxic and frequently also mutagenic, and are employed for chemotherapy of certain cancers. All organisms have multiple DNA repair strategies to counteract the effects of DNA alkylation. To defend against fluctuating levels of environmental alkylating agents, many bacteria mount an inducible response that enhances cellular resistance to these same agents. This adaptive response has been most extensively studied in E. coli, in which induced alkylation resistance results from increased expression of four genes, ada, alkB, alkA and aidB. The Ada, AlkA and AlkB proteins protect against alkylation by repair of methylated bases in DNA using different mechanisms, whereas AidB may directly destroy certain alkylating agents. These DNA repair activities are conserved from bacteria to man. The Ada protein also serves as the positive regulator of ‘the adaptive response to alkylation damage’, which is more concisely named ‘the Ada response’ by analogy with the SOS, SoxRS and OxyR responses. Various aspects of the Ada response have been the subject of previous detailed reviews (Friedberg et al., 1995; Landini and Volkert, 2000; Lindahl et al., 1988; Samson, 1992; Sedgwick and Vaughan, 1991; Seeberg and Berdal, 1999). Here, we describe the properties of the inducible proteins with particular emphasis on recent findings, such as those from genome sequencing, protein structural studies, analysis of substrate specificities, and the newly discovered function of the AlkB protein.

Conservation of the Ada response in many bacterial species suggests the presence of direct alkylating agents in their environment. Good candidate agents are those produced by microorganisms, but others may be formed by chemical reactions. Some Streptomyces sp. release alkylating antibiotics, such as streptozotocin (a derivative of MNU) and azaserine (O-diazoacyl-L-serine), into the soil creating an urgent need for an adaptive response in other microorganisms. Furthermore, certain algae and fungi growing in saline environments generate MeCl as a product of chloride detoxification (Sedgwick and Vaughan, 1991). MeCl is probably the most abundant methylating agent in our environment (Crutzen and Andreae, 1990). Chemically, direct acting alkylating agents may be formed by nitrosations, in slightly acidic conditions, of amides, amines, amino acids and peptides (Harrison et al., 1999; Sedgwick, 1997; Sedgwick and Vaughan, 1991). These reactions could possibly occur in decaying matter, in acidic soils or in putrid water.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 7
Figure 6

References

  • Akimaru H, Sakumi K, Yoshikai T, Anai M, Sekiguchi M . 1990 J. Mol. Biol. 216: 261–273

  • Aravind L, Koonin EV . 2001 Genome Biol. 2: Research 0007

  • Berdal KG, Johansen RF, Seeberg E . 1998 EMBO J. 17: 363–367

  • Bhasin N, Ghosh A . 1995 Mutat. Res. 336: 79–89

  • Bodell WJ, Singer B . 1979 Biochemistry 18: 2860–2863

  • Boiteux S, Laval J . 1982 Biochimie 64: 637–641

  • Calmels S, Ohshima H, Rosenkranz H, McCoy E, Bartsch H . 1987 Carcinogenesis 8: 1085–1088

  • Chen BJ, Carroll P, Samson L . 1994 J. Bacteriol. 176: 6255–6261

  • Cheng X, Roberts RJ . 2001 Nucleic Acids Res. 29: 3784–3795

  • Clarke ND, Kvaal M, Seeberg E . 1984 Mol. Gen. Genet. 197: 368–372

  • Colombi D, Gomes SL . 1997 J. Bacteriol. 179: 3139–3145

  • Crutzen PJ, Andreae MO . 1990 Science 250: 1669–1678

  • Daniels DS, Tainer JA . 2000 Mutat. Res. 460: 151–163

  • Demple B, Sedgwick B, Robins P, Totty N, Waterfield MD, Lindahl T . 1985 Proc. Natl. Acad. Sci. USA 82: 2688–2692

  • Dinglay S, Trewick SC, Lindahl T, Sedgwick B . 2000 Genes Dev. 14: 2097–2105

  • Falnes PO, Johansen RF, Seeberg E . 2002 Nature 419: 178–181

  • Friedberg E, Walker G, Siede W . 1995 DNA Repair and Mutagenesis Washington, D.C.: ASM Press

    Google Scholar 

  • Gasparutto D, Dherin C, Boiteux B, Cadet J . 2002 DNA Repair 1: 437–447

  • Harrison KL, Jukes R, Cooper DP, Shuker DEG . 1999 Chem. Res. Toxicol. 12: 106–111

  • Hix S, Morais MS, Augusto O . 1995 Free Radical Bio. Med. 19: 293–301

  • Hollis T, Lau A, Ellenberger T . 2000 Mutat. Res. 460: 201–210

  • Kataoka H, Yamamoto Y, Sekiguchi M . 1983 J. Bacteriol. 153: 1301–1307

  • Kunisaki N, Hayashi M . 1979 Appl. Envir. Microbiol. 37: 279–282

  • Labahn J, Scharer OD, Long A, Ezaz-Nikpay K, Verdine GL, Ellenberger TE . 1996 Cell 86: 321–329

  • Landini P, Hajec LI, Volkert MR . 1994 J. Bacteriol. 176: 6583–6589

  • Landini P, Volkert MR . 2000 J. Bacteriol. 182: 6543–6549

  • Larson K, Sahm J, Shenkar R, Strauss B . 1985 Mutat. Res. 150: 77–84

  • Lin Y, Dotsch V, Wintner T, Peariso K, Myers LC, Penner-Hahn JE, Verdine GL, Wagner G . 2001 Biochemistry 40: 4261–4271

  • Lindahl T, Sedgwick B, Sekiguchi M, Nakabeppu Y . 1988 Ann. Rev. Biochem. 57: 133–157

  • Lizcano MJ, Unzeta M, Tipton KF . 2000 Anal. Biochem. 286: 75–79

  • Marcotte EM, Pellegrini M, Ng H-L, Rice DW, Yeates TO, Eisenberg D . 1999 Science 285: 751–753

  • Matthews RG, Goulding CW . 1997 Curr. Opin. Chem. Biol. 1: 332–339

  • Monti P, Campomenosi P, Ciribilli Y, Iannone R, Inga A, Shah D, Scott G, Burns PA, Menichini P, Abbondandolo A, Gold B, Fronza G . 2002 J. Biol. Chem. 277: 28663–28668

  • Moore MH, Gulbis JM, Dobson EJ, Demple B, Moody PCE . 1994 EMBO J. 13: 1495–1501

  • Morohoshi F, Hayashi K, Munakata N . 1993 J. Bacteriol. 175: 6010–6017

  • Morohoshi F, Munakata N . 1995 Mutat. Res. 337: 97–110

  • Myers LC, Verdine GL . 1994 Curr. Opin. Struct. Biol. 4: 51–59

  • O'Rourke EJ, Chevalier C, Boiteux S, Labigne A, Ielp L, Radicella JP . 2000 J. Biol. Chem. 275: 20077–20083

  • Posnick LM, Samson LD . 1999a J. Bacteriol. 181: 6763–6771

  • Posnick LM, Samson LD . 1999b J. Bacteriol. 181: 6756–6762

  • Potter PM, Kleibl K, Cawkwell L, Margison GP . 1989 Nucleic Acids Res. 17: 8047–8060

  • Prescott AG, Lloyd MD . 2000 Nat. Prod. Rep. 17: 367–383

  • Privezentzev CV, Saparbaev M, Sambandam A, Greenberg MM, Laval J . 2000 Biochemistry 39: 14263–14268

  • Rebeck GW, Smith CM, Goad DL, Samson L . 1989 J. Bacteriol. 171: 4563–4568

  • Rebeil R, Nicholson WL . 2001 Proc. Natl. Acad. Sci. USA 98: 9038–9043

  • Ryle MJ, Hausinger RP . 2002 Curr. Opin. Chem. Biol. 6: 193–201

  • Saget BM, Walker GC . 1994 Proc. Natl. Acad. Sci. USA 91: 9730–9734

  • Sakashita H, Sakuma T, Akitomo Y, Ohkubo T, Kainosho M, Sekiguchi M, Morikawa K . 1995 Proc. Japan Acad. 71: 198–201

  • Sakumi K, Sekiguchi M . 1989 J. Mol. Biol. 205: 373–385

  • Samson L . 1992 Mol. Microbiol. 6: 825–831

  • Sancar A . 1996 Annu. Rev. Biochem. 65: 43–81

  • Schofield CJ, Zhang Z . 1999 Curr. Opin. Struct. Biol. 9: 722–731

  • Sedgwick B . 1997 Carcinogenesis 18: 1561–1567

  • Sedgwick B, Robins P, Totty N, Lindahl T . 1988 J. Biol. Chem. 263: 4430–4433

  • Sedgwick B, Vaughan P . 1991 Mutat. Res. 250: 211–221

  • Seeberg E, Berdal KG . 1999 Base Excision Repair of DNA Damage: Repair of Alkylation Damage to DNA Hickson I (ed) Austin, TX: Landes Bioscience pp 151–168

    Google Scholar 

  • Singer B, Grunberger D . 1983 Molecular Biology of Mutagens and Carcinogens: Reactions of Directly Acting Agents with Nucleic Acids New York: Plenum Press

    Book  Google Scholar 

  • Takahashi K, Kawazoe Y . 1987 Mutat. Res. 180: 163–169

  • Taverna P, Sedgwick B . 1996 J. Bacteriol. 178: 5105–5111

  • Teo I, Sedgwick B, Kilpatrick MW, McCarthy TV, Lindahl T . 1986 Cell 45: 315–324

  • Thornburg LD, Lai M-T, Wishnok JS, Stubbe J . 1993 Biochemistry 32: 14023–14033

  • Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B . 2002 Nature 419: 174–178

  • Vaughan P, Lindahl T, Sedgwick B . 1993 Mutat. Res. 293: 249–257

  • Vaughan P, Sedgwick B, Hall J, Gannon J, Lindahl T . 1991 Carcinogenesis 12: 263–268

  • Volkert MR, Hajec LI, Matijasevic Z, Fang FC, Prince R . 1994 J. Bacteriol. 176: 7638–7645

  • Vora RA, Pegg AE, Ealick SE . 1998 Proteins: Struct. Funct. Genet. 32: 3–6

  • Wei Y-F, Chen BJ, Samson L . 1995 J. Bacteriol. 177: 5009–5015

  • Yamagata Y, Kato M, Odawara K, Tokuno Y, Nakashima Y, Matsushima N, Yasumura K, Tomita K, Ihara K, Fujii Y, Nakabeppu Y, Sekiguchi M, Fujii S . 1996 Cell 86: 311–319

  • Yamamoto Y, Katsuki M, Sekiguchi M, Otsuji N . 1978 J. Bacteriol. 135: 144–152

  • Yang CS, Smith TJ . 1996 Biological Reactive Intermediates V Snyder R (ed) New York: Plenum Press pp 385–394

    Book  Google Scholar 

  • Zhang Z, Ren J, Stammers D, Baldwin JE, Harlos K, Schofield CJ . 2000 Nature Structural Biol. 7: 127–133

Download references

Author information

Authors and Affiliations

  1. Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, EN6 3LD, Hertfordshire, UK

    Barbara Sedgwick & Tomas Lindahl

Authors
  1. Barbara Sedgwick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomas Lindahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tomas Lindahl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sedgwick, B., Lindahl, T. Recent progress on the Ada response for inducible repair of DNA alkylation damage. Oncogene 21, 8886–8894 (2002). https://doi.org/10.1038/sj.onc.1205998

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205998

Keywords

This article is cited by

Search

Advanced search

Quick links