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.
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Data are deposited at ArrayExpress under the accession number E-MTAB-1689.
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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).
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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.
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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
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DOI: https://doi.org/10.1038/nature12452
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