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Cytosine-5-methyltransferases add aldehydes to DNA

Abstract

Targeted methylation of cytosine residues by S-adenosylmethionine–dependent DNA methyltransferases modulates gene expression in vertebrates. Here we show that cytosine-5-methyltransferases catalyze reversible covalent addition of exogenous aliphatic aldehydes to their target residues in DNA, thus yielding corresponding 5-α-hydroxyalkylcytosines. Such atypical enzymatic reactions with non-cofactor-like substrates open new ways for sequence-specific derivatization of DNA and demonstrate enzymatic exchange of 5-hydroxymethyl groups on cytosine in support of an oxidative mechanism of DNA demethylation.

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Figure 1: Reversible covalent modifications of cytosine with aliphatic aldehydes in the presence of a DNA C5-MTase.

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References

  1. Goll, M.G. & Bestor, T.H. Annu. Rev. Biochem. 74, 481–514 (2005).

    Article  CAS  Google Scholar 

  2. Morgan, H.D., Santos, F., Green, K., Dean, W. & Reik, W. Hum. Mol. Genet. 14, R47–R58 (2005).

    Article  CAS  Google Scholar 

  3. Klimasauskas, S. & Weinhold, E. Trends Biotechnol. 25, 99–104 (2007).

    Article  CAS  Google Scholar 

  4. Klimasauskas, S. & Lukinavicius, G. in Wiley Encyclopedia of Chemical Biology (ed. Begley, T.P.) Ch. 335 (John Wiley & Sons, New York, 2008).

  5. Wu, J.C. & Santi, D.V. J. Biol. Chem. 262, 4778–4786 (1987).

    CAS  PubMed  Google Scholar 

  6. Bujnicki, J.M., Feder, M., Ayres, C.L. & Redman, K.L. Nucleic Acids Res. 32, 2453–2463 (2004).

    Article  CAS  Google Scholar 

  7. Graves, K.L., Butler, M.M. & Hardy, L.W. Biochemistry 31, 10315–10321 (1992).

    Article  CAS  Google Scholar 

  8. Cheng, X. & Roberts, R.J. Nucleic Acids Res. 29, 3784–3795 (2001).

    Article  CAS  Google Scholar 

  9. Zingg, J.-M., Shen, J.-C., Yang, A.S., Rapoport, H. & Jones, P.A. Nucleic Acids Res. 24, 3267–3275 (1996).

    Article  CAS  Google Scholar 

  10. Solomon, M.J. & Varshavsky, A. Proc. Natl. Acad. Sci. USA 82, 6470–6474 (1985).

    Article  CAS  Google Scholar 

  11. Daujotyte, D., Liutkeviciute, Z., Tamulaitis, G. & Klimasauskas, S. Nucleic Acids Res. 36, e57 (2008).

    Article  Google Scholar 

  12. Roberts, R.J., Vincze, T., Posfai, J. & Macelis, D. Nucleic Acids Res. 35, D269–D270 (2007).

    Article  CAS  Google Scholar 

  13. Bornscheuer, U.T. & Kazlauskas, R.J. Angew. Chem. Int. Ed. 43, 6032–6040 (2004).

    Article  CAS  Google Scholar 

  14. Wang, M., Cheng, G., Villalta, P.W. & Hecht, S.S. Chem. Res. Toxicol. 20, 1141–1148 (2007).

    Article  CAS  Google Scholar 

  15. Kusmierek, J.T. & Singer, B. Biochemistry 21, 5717–5722 (1982).

    Article  CAS  Google Scholar 

  16. Klimasauskas, S., Kumar, S., Roberts, R.J. & Cheng, X. Cell 76, 357–369 (1994).

    Article  CAS  Google Scholar 

  17. Lukinavicius, G. et al. J. Am. Chem. Soc. 129, 2758–2759 (2007).

    Article  CAS  Google Scholar 

  18. Gommers-Ampt, J.H. & Borst, P. FASEB J. 9, 1034–1042 (1995).

    Article  CAS  Google Scholar 

  19. Privat, E. & Sowers, L.C. Chem. Res. Toxicol. 9, 745–750 (1996).

    Article  CAS  Google Scholar 

  20. Tahiliani, M. et al. Science published online, doi:10.1126/science.1170116 (16 April 2009).

  21. Kriaucionis, S. & Heintz, N. Science published online, doi:10.1126/science.1169786 (16 April 2009).

  22. Heck, H. & Casanova, M. Regul. Toxicol. Pharmacol. 40, 92–106 (2004).

    Article  CAS  Google Scholar 

  23. Prescher, J.A. & Bertozzi, C.R. Nat. Chem. Biol. 1, 13–21 (2005).

    Article  CAS  Google Scholar 

  24. Chittaboina, S., Xie, F. & Wang, Q. Tetrahedron Lett. 46, 2331–2336 (2005).

    Article  CAS  Google Scholar 

  25. Sedgwick, B., Bates, P.A., Paik, J., Jacobs, S.C. & Lindahl, T. DNA Repair (Amst.) 6, 429–442 (2007).

    Article  CAS  Google Scholar 

  26. Hamm, S. et al. Bioorg. Med. Chem. Lett. 18, 1046–1049 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Moréra (Laboratoire d'Enzymologie et Biochimie Structurales) and L.C. Sowers (Loma Linda University) for the gift of an hmC-containing oligonucleotide, G. Vilkaitis (Institute of Biotechnology) for a sample of mouse Dnmt1, and M. Petrusõytė (Fermentas) for M.HpaII. Thanks are due to L. Peil for HR-MS analysis of modified nucleosides, M. Krenevicõienė for NMR spectra and E. Weinhold for valuable discussions. This work was supported by grants from the Lithuanian State Science and Study Foundation and the Ministry of Education and Science of Lithuania.

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Correspondence to Saulius Klimašauskas.

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Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 1373 kb)

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Liutkevičiūtė, Z., Lukinavičius, G., Masevičius, V. et al. Cytosine-5-methyltransferases add aldehydes to DNA. Nat Chem Biol 5, 400–402 (2009). https://doi.org/10.1038/nchembio.172

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