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 damage in germ cells induces an innate immune response that triggers systemic stress resistance

Abstract

DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis1. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell divisions, whereas somatic tissues are entirely post-mitotic. Consequently, DNA damage checkpoints function specifically in the germ line2, whereas somatic tissues in adult C. elegans are highly radio-resistant3. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells4. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin–proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: DNA damage in the germ line leads to somatic stress resistance.
Figure 2: Stress resistance induced by germline DNA damage is mediated through MPK- 1.
Figure 3: Somatic stress resistance after DNA damage in germ cells is mediated through MPK-1-induced functional innate immune response.
Figure 4: Innate immune responses trigger UPS activation to confer systemic stress resistance.

Accession codes

Accessions

ArrayExpress

Data deposits

Data are deposited at ArrayExpress under the accession number E-MTAB-1689.

References

  1. Bartek, J. & Lukas, J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr. Opin. Cell Biol. 19, 238–245 (2007)

    CAS  Article  Google Scholar 

  2. Gartner, A., Milstein, S., Ahmed, S., Hodgkin, J. & Hengartner, M. O. A conserved checkpoint pathway mediates DNA damage—induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell 5, 435–443 (2000)

    CAS  Article  Google Scholar 

  3. Johnson, T. E. & Hartman, P. S. Radiation effects on life span in Caenorhabditis elegans. J. Gerontol. 43, B137–B141 (1988)

    CAS  Article  Google Scholar 

  4. Lans, H. et al. Involvement of global genome repair, transcription coupled repair, and chromatin remodeling in UV DNA damage response changes during development. PLoS Genet. 6, e1000941 (2010)

    Article  Google Scholar 

  5. Hsu, A. L., Murphy, C. T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003)

    ADS  CAS  Article  Google Scholar 

  6. Garcia-Muse, T. & Boulton, S. J. Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans. EMBO J. 24, 4345–4355 (2005)

    CAS  Article  Google Scholar 

  7. Moser, S. C. et al. Functional dissection of Caenorhabditis elegans CLK-2/TEL2 cell cycle defects during embryogenesis and germline development. PLoS Genet. 5, e1000451 (2009)

    Article  Google Scholar 

  8. Colaiácovo, M. P. et al. Synaptonemal complex assembly in C. elegans is dispensable for loading strand-exchange proteins but critical for proper completion of recombination. Dev. Cell 5, 463–474 (2003)

    Article  Google Scholar 

  9. Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nature Genet. 28, 139–145 (2001)

    CAS  Article  Google Scholar 

  10. Yamawaki, T. M. et al. The somatic reproductive tissues of C. elegans promote longevity through steroid hormone signaling. PLoS Biol. 8, e1000468 (2010)

    Article  Google Scholar 

  11. Rutkowski, R. et al. Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling. PLoS Genet. 7, e1002238 (2011)

    CAS  Article  Google Scholar 

  12. Karpac, J., Younger, A. & Jasper, H. Dynamic coordination of innate immune signaling and insulin signaling regulates systemic responses to localized DNA damage. Dev. Cell 20, 841–854 (2011)

    CAS  Article  Google Scholar 

  13. Dent, P., Yacoub, A., Fisher, P. B., Hagan, M. P. & Grant, S. MAPK pathways in radiation responses. Oncogene 22, 5885–5896 (2003)

    CAS  Article  Google Scholar 

  14. Greiss, S., Schumacher, B., Grandien, K., Rothblatt, J. & Gartner, A. Transcriptional profiling in C. elegans suggests DNA damage dependent apoptosis as an ancient function of the p53 family. BMC Genomics 9, 334 (2008)

    Article  Google Scholar 

  15. Shivers, R. P., Youngman, M. J. & Kim, D. H. Transcriptional responses to pathogens in Caenorhabditis elegans. Curr. Opin. Microbiol. 11, 251–256 (2008)

    CAS  Article  Google Scholar 

  16. Nicholas, H. R. & Hodgkin, J. The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans. Curr. Biol. 14, 1256–1261 (2004)

    CAS  Article  Google Scholar 

  17. O'Rourke, D., Baban, D., Demidova, M., Mott, R. & Hodgkin, J. Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res. 16, 1005–1016 (2006)

    CAS  Article  Google Scholar 

  18. Troemel, E. R. et al. p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet. 2, e183 (2006)

    Article  Google Scholar 

  19. Irazoqui, J. E., Urbach, J. M. & Ausubel, F. M. Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nature Rev. Immunol. 10, 47–58 (2010)

    CAS  Article  Google Scholar 

  20. Thomas, J. H. Concerted evolution of two novel protein families in Caenorhabditis species. Genetics 172, 2269–2281 (2006)

    CAS  Article  Google Scholar 

  21. Shivers, R. P. et al. Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans. PLoS Genet. 6, e1000892 (2010)

    Article  Google Scholar 

  22. Shivers, R. P., Kooistra, T., Chu, S. W., Pagano, D. J. & Kim, D. H. Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. Cell Host Microbe 6, 321–330 (2009)

    CAS  Article  Google Scholar 

  23. Segref, A., Torres, S. & Hoppe, T. A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. Genetics 187, 1235–1240 (2011)

    CAS  Article  Google Scholar 

  24. Muruve, D. A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008)

    ADS  CAS  Article  Google Scholar 

  25. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005)

    ADS  CAS  Article  Google Scholar 

  26. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biol. 11, 973–979 (2009); erratum. 11, 973–979 (2009)

    CAS  Article  Google Scholar 

  27. Iizuka, M. & Konno, S. Wound healing of intestinal epithelial cells. World J. Gastroenterol. 11, 1272 (2009)

    Google Scholar 

  28. Gregorio, J. et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J. Exp. Med. 207, 2921–2930 (2010)

    CAS  Article  Google Scholar 

  29. Richardson, C. E., Kooistra, T. & Kim, D. H. An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463, 1092–1095 (2010)

    ADS  CAS  Article  Google Scholar 

  30. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974)

    CAS  Article  Google Scholar 

  31. Kim, D. H. et al. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297, 623–626 (2002)

    ADS  CAS  Article  Google Scholar 

  32. Petersen, T. N., Brunak, S., von Heijne, G. & Nielsen, H. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nature Methods 8, 785–786 (2011)

    CAS  Article  Google Scholar 

  33. Horton, P. et al. WoLF PSORT: protein localization predictor. Nucleic Acids Res. 35, W585–W587 (2007)

    Article  Google Scholar 

  34. Bush, K. T., Goldberg, A. L. & Nigam, S. K. Proteasome inhibition leads to a heat-shock response, induction of endoplasmic reticulum chaperones, and thermotolerance. J. Biol. Chem. 272, 9086–9092 (1997)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank S. Torres for technical support, P. Frommolt for advice on statistics, and A. Williams for comments on the manuscript. C. elegans strains were kindly provided by the CGC (funded by the US National Institutes of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440)), and the Mitani laboratory. We thank D. Kim, F. Ausubel and V. Jantsch for strains and reagents. M.A.E. received the European Molecular Biology Organization (EMBO) long-term fellowship, A.D. received the IGS-DHD fellowship, and H.-L.O. received the CECAD fellowship. O.U. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG) (SFB 670-TP4), and T.H. from the EC Network of Excellence RUBICON (LSHC-CT-2005-018683), DFG (CECAD, FOR885, SFB635, KFO286 and HO2541/4-1). B.S. acknowledges funding from the DFG (CECAD, SFB 829 and KFO 286), European Research Council (starting grant 260383), Marie Curie (FP7 ITN CodeAge 316354, aDDRess 316390, MARRIAGE 316964 and ERG 239330), German–Israeli Foundation (GIF 2213-1935.13/2008 and 1104-68.11/2010), Deutsche Krebshilfe (109453) and BMBF (SyBaCol).

Author information

Affiliations

Authors

Contributions

M.A.E. and B.S. designed the study and analysed data; M.A.E., A.S., A.D., H.-L.O. and J.I.S. performed experiments and discussed data; A.S. and T.H. designed UPS-specific experiments; O.U. provided advice and reagents; and B.S. wrote the manuscript.

Corresponding author

Correspondence to Björn Schumacher.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15 and Supplementary Tables 1-4. (PDF 3009 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ermolaeva, M., Segref, A., Dakhovnik, A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013). https://doi.org/10.1038/nature12452

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12452

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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