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.

DNA–protein crosslink repair

Abstract

DNA–protein crosslinks (DPCs) are highly toxic DNA adducts, but whether dedicated DPC-repair mechanisms exist was until recently unknown. This has changed with discoveries made in yeast and Xenopus laevis that revealed a protease-based DNA-repair pathway specific for DPCs. Importantly, mutations in the gene encoding the putative human homologue of a yeast DPC protease cause a human premature ageing and cancer predisposition syndrome. Thus, DPC repair is a previously overlooked genome-maintenance mechanism that may be essential for tumour suppression.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The formation of DPCs.
Figure 2: Consequences and characteristics of DPCs.
Figure 3: Modes of DPC repair and tolerance.

References

  1. 1

    Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009).

    CAS  Article  Google Scholar 

  2. 2

    Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Barker, S., Weinfeld, M. & Murray, D. DNA–protein crosslinks: their induction, repair, and biological consequences. Mutat. Res. 589, 111–135 (2005).

    CAS  Article  Google Scholar 

  4. 4

    Stingele, J., Schwarz, M. S., Bloemeke, N., Wolf, P. G. & Jentsch, S. A. DNA-dependent protease involved in DNA-protein crosslink repair. Cell 158, 327–338 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Duxin, J. P., Dewar, J. M., Yardimci, H. & Walter, J. C. Repair of a DNA-protein crosslink by replication-coupled proteolysis. Cell 159, 346–357 (2014).

    CAS  Article  Google Scholar 

  6. 6

    Kiianitsa, K. & Maizels, N. A rapid and sensitive assay for DNA–protein covalent complexes in living cells. Nucleic Acids Res. 41, e104 (2013).

    CAS  Article  Google Scholar 

  7. 7

    Chen, S. H., Chan, N. L. & Hsieh, T. S. New mechanistic and functional insights into DNA topoisomerases. Annu. Rev. Biochem. 82, 139–170 (2013).

    CAS  Article  Google Scholar 

  8. 8

    Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer 6, 789–802 (2006).

    CAS  Article  Google Scholar 

  9. 9

    Pourquier, P. et al. Effects of uracil incorporation, DNA mismatches, and abasic sites on cleavage and religation activities of mammalian topoisomerase I. J. Biol. Chem. 272, 7792–7796 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Pommier, Y. et al. Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA Repair 19, 114–129 (2014).

    CAS  Article  Google Scholar 

  11. 11

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Shen, L., Song, C. X., He, C. & Zhang, Y. Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu. Rev. Biochem. 83, 585–614 (2014).

    CAS  Article  Google Scholar 

  14. 14

    Trewick, S. C., Henshaw, T. F., Hausinger, R. P., Lindahl, T. & Sedgwick, B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 419, 174–178 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Solomon, M. J., Larsen, P. L. & Varshavsky, A. Mapping protein-DNA interactions in vivo with formaldehyde: evidence that histone H4 is retained on a highly transcribed gene. Cell 53, 937–947 (1988).

    CAS  Article  Google Scholar 

  16. 16

    Lu, K. et al. Structural characterization of formaldehyde-induced cross-links between amino acids and deoxynucleosides and their oligomers. J. Am. Chem. Soc. 132, 3388–3399 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Ward, J. F. The complexity of DNA damage: relevance to biological consequences. Int. J. Radiat. Biol. 66, 427–432 (1994).

    CAS  Article  Google Scholar 

  18. 18

    Zhang, H., Koch, C. J., Wallen, C. A. & Wheeler, K. T. Radiation-induced DNA damage in tumors and normal tissues. III. Oxygen dependence of the formation of strand breaks and DNA-protein crosslinks. Radiat. Res. 142, 163–168 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Fornace, A. J. Jr & Little, J. B. DNA crosslinking induced by X-rays and chemical agents. Biochim. Biophys. Acta 477, 343–355 (1977).

    CAS  Article  Google Scholar 

  20. 20

    Shoulkamy, M. I. et al. Detection of DNA–protein crosslinks (DPCs) by novel direct fluorescence labeling methods: distinct stabilities of aldehyde and radiation-induced DPCs. Nucleic Acids Res. 40, e143 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Nitiss, J. L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer 9, 338–350 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Nakano, T. et al. T7 RNA polymerases backed up by covalently trapped proteins catalyze highly error prone transcription. J. Biol. Chem. 287, 6562–6572 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Nakano, T. et al. Translocation and stability of replicative DNA helicases upon encountering DNA–protein cross-links. J. Biol. Chem. 288, 4649–4658 (2013).

    CAS  Article  Google Scholar 

  24. 24

    Fu, Y. V. et al. Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146, 931–941 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Kuo, H. K., Griffith, J. D. & Kreuzer, K. N. 5-azacytidine induced methyltransferase-DNA adducts block DNA replication in vivo. Cancer Res. 67, 8248–8254 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Yeo, J. E. et al. Synthesis of site-specific DNA-protein conjugates and their effects on DNA replication. ACS Chem. Biol. 9, 1860–1868 (2014).

    CAS  Article  Google Scholar 

  27. 27

    Novakova, O., Kasparkova, J., Malina, J., Natile, G. & Brabec, V. DNA–protein cross-linking by trans-[PtCl2(E-iminoether)2]. A concept for activation of the trans geometry in platinum antitumor complexes. Nucleic Acids Res. 31, 6450–6460 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Chvalova, K., Brabec, V. & Kasparkova, J. Mechanism of the formation of DNA–protein cross-links by antitumor cisplatin. Nucleic Acids Res. 35, 1812–1821 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Titenko-Holland, N. et al. Quantification of epithelial cell micronuclei by fluorescence in situ hybridization (FISH) in mortuary science students exposed to formaldehyde. Mutat. Res. 371, 237–248 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Basler, A., v d Hude, W. & Scheutwinkel-Reich, M. Formaldehyde-induced sister chromatid exchanges in vitro and the influence of the exogenous metabolizing systems S9 mix and primary rat hepatocytes. Arch. Toxicol. 58, 10–13 (1985).

    CAS  Article  Google Scholar 

  31. 31

    Grogan, D. & Jinks-Robertson, S. Formaldehyde-induced mutagenesis in Saccharomyces cerevisiae: molecular properties and the roles of repair and bypass systems. Mutat. Res. 731, 92–98 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Swenberg, J. A. et al. Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol. Sci. 120, S130–S145 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Hartsuiker, E., Neale, M. J. & Carr, A. M. Distinct requirements for the Rad32Mre11 nuclease and Ctp1CtIP in the removal of covalently bound topoisomerase I and II from DNA. Mol. Cell 33, 117–123 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Hartsuiker, E. et al. Ctp1CtIP and Rad32Mre11 nuclease activity are required for Rec12Spo11 removal, but Rec12Spo11 removal is dispensable for other MRN-dependent meiotic functions. Mol. Cell. Biol. 29, 1671–1681 (2009).

    CAS  Article  Google Scholar 

  35. 35

    Cannavo, E. & Cejka, P. Sae2 promotes dsDNA endonuclease activity within Mre11-Rad50-Xrs2 to resect DNA breaks. Nature 514, 122–125 (2014).

    CAS  Article  Google Scholar 

  36. 36

    de Graaf, B., Clore, A. & McCullough, A. K. Cellular pathways for DNA repair and damage tolerance of formaldehyde-induced DNA-protein crosslinks. DNA Repair 8, 1207–1214 (2009).

    CAS  Article  Google Scholar 

  37. 37

    Nakano, T. et al. Homologous recombination but not nucleotide excision repair plays a pivotal role in tolerance of DNA-protein cross-links in mammalian cells. J. Biol. Chem. 284, 27065–27076 (2009).

    CAS  Article  Google Scholar 

  38. 38

    Nakano, T. et al. Nucleotide excision repair and homologous recombination systems commit differentially to the repair of DNA-protein crosslinks. Mol. Cell 28, 147–158 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Fornace, A. J. Jr. Detection of DNA single-strand breaks produced during the repair of damage by DNA-protein cross-linking agents. Cancer Res. 42, 145–149 (1982).

    CAS  PubMed  Google Scholar 

  40. 40

    Baker, D. J. et al. Nucleotide excision repair eliminates unique DNA-protein cross-links from mammalian cells. J. Biol. Chem. 282, 22592–22604 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Quievryn, G. & Zhitkovich, A. Loss of DNA–protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. Carcinogenesis 21, 1573–1580 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Ridpath, J. R. et al. Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res. 67, 11117–11122 (2007).

    CAS  Article  Google Scholar 

  43. 43

    Orta, M. L. et al. 5-Aza-2′-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair. Nucleic Acids Res. 41, 5827–5836 (2013).

    CAS  Article  Google Scholar 

  44. 44

    Rosado, I. V., Langevin, F., Crossan, G. P., Takata, M. & Patel, K. J. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway. Nat. Struct. Mol. Biol. 18, 1432–1434 (2011).

    CAS  Article  Google Scholar 

  45. 45

    Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J. & Patel, K. J. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475, 53–58 (2011).

    CAS  Article  Google Scholar 

  46. 46

    Garaycoechea, J. I. et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489, 571–575 (2012).

    CAS  Article  Google Scholar 

  47. 47

    Stingele, J., Habermann, B. & Jentsch, S. DNA–protein crosslink repair: proteases as DNA repair enzymes. Trends Biochem. Sci. 40, 67–71 (2015).

    CAS  Article  Google Scholar 

  48. 48

    Centore, R. C., Yazinski, S. A., Tse, A. & Zou, L. Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Mol. Cell 46, 625–635 (2012).

    CAS  Article  Google Scholar 

  49. 49

    Fang, Q. DNA–protein crosslinks processed by nucleotide excision repair and homologous recombination with base and strand preference in E. coli model system. Mutat. Res. 741–742, 1–10 (2013).

    Article  Google Scholar 

  50. 50

    Davis, E. J. et al. DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nat. Struct. Mol. Biol. 19, 1093–1100 (2012).

    CAS  Article  Google Scholar 

  51. 51

    Juhasz, S. et al. Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic Acids Res. 40, 10795–10808 (2012).

    CAS  Article  Google Scholar 

  52. 52

    Machida, Y., Kim, M. S. & Machida, Y. J. Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell Cycle 11, 3395–3402 (2012).

    CAS  Article  Google Scholar 

  53. 53

    Ghosal, G., Leung, J. W., Nair, B. C., Fong, K. W. & Chen, J. Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J. Biol. Chem. 287, 34225–34233 (2012).

    CAS  Article  Google Scholar 

  54. 54

    Delabaere, L. et al. The spartan ortholog maternal haploid is required for paternal chromosome integrity in the Drosophila zygote. Curr. Biol. 24, 2281–2287 (2014).

    CAS  Article  Google Scholar 

  55. 55

    Lessel, D. et al. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat. Genet. 46, 1239–1244 (2014).

    CAS  Article  Google Scholar 

  56. 56

    Maskey, R. S. et al. Spartan deficiency causes genomic instability and progeroid phenotypes. Nat. Commun. 5, 5744 (2014).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

S.J. is supported by the Max Planck Society, Deutsche Forschungsgemeinschaft, Center for Integrated Protein Science Munich, RUBICON EU Network of Excellence, a European Research Council Advanced Grant and the Louis-Jeantet Foundation.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Julian Stingele or Stefan Jentsch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (figure)

The detection and characterization of DNA–protein crosslinks. (PDF 144 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stingele, J., Jentsch, S. DNA–protein crosslink repair. Nat Rev Mol Cell Biol 16, 455–460 (2015). https://doi.org/10.1038/nrm4015

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing