Abstract
DNA damage causes cancer, impairs development and accelerates aging. Transcription-blocking lesions and transcription-coupled repair defects lead to developmental failure and premature aging in humans. Following DNA repair, homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Here, we report that, in Caenorhabditis elegans, removal of the WRAD complex of the MLL/COMPASS H3K4 methyltransferase exacerbates developmental growth retardation and accelerates aging, while depletion of the H3K4 demethylases SPR-5 and AMX-1 promotes developmental growth and extends lifespan amid ultraviolet-induced damage. We demonstrate that DNA-damage-induced H3K4me2 is associated with the activation of genes regulating RNA transport, splicing, ribosome biogenesis and protein homeostasis and regulates the recovery of protein biosynthesis that ensures survival following genotoxic stress. Our study uncovers a role for H3K4me2 in coordinating the recovery of protein biosynthesis and homeostasis required for developmental growth and longevity after DNA damage.
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Acknowledgements
We thank the CECAD imaging, proteomics and bioinformatics facilities and the Cologne Center for Genomics (CCG) for support. Worm strains were provided by the National Bioresource Project (supported by The Ministry of Education, Culture, Sports, Science and Technology, Japan), the Caenorhabditis Genetics Center (funded by the NIH National Center for Research Resources, USA), and the C. elegans Gene Knockout Project at the Oklahoma Medical Research Foundation (part of the International C. elegans Gene Knockout Consortium). We furthermore thank the Regional Computing Center of the University of Cologne (RRZK) for providing computing time on the DFG-funded High Performance Computing (HPC) system CHEOPS, as well as support. B.S. acknowledges funding from the Deutsche Forschungsgemeinschaft (SCHU 2494/3-1, SCHU 2494/7-1, SCHU 2494/10-1, SCHU 2494/11-1, CECAD, SFB 829, SFB 670, KFO 286, KFO 329 and GRK2407), Deutsche Krebshilfe (70112899) and the H2020-MSCA-ITN-2018 (HealthAge and aDDRess Innovative Training Networks).
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S.W. designed the study, performed all experiments and analyzed the data, D.M. performed all bioinformatics analysis. B.S. coordinated the project and, together with S.W., designed the study. All authors contributed to writing the manuscript.
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Supplementary Information
Supplementary Figs. 1–6.
Supplementary Table 1
List of chromatin remodeling factors investigated in Fig. 1a.
Supplementary Table 2
List of significantly enriched genes that show an increase in H3K4me2 deposition (ChIP–seq) and in transcription (RNA-seq) at 24-h post-UV treatment or mock-treatment.
Supplementary Table 3
List of genes that have changes in H3K4me2 deposition (ChIP–seq), transcription (RNA-seq) and proteomics (isotope labeling assay).
Supplementary Data 1
Uncropped western blot images.
Supplementary Data 2
Statistical source data for graphs in this paper.
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Wang, S., Meyer, D.H. & Schumacher, B. H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage. Nat Struct Mol Biol 27, 1165–1177 (2020). https://doi.org/10.1038/s41594-020-00513-1
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DOI: https://doi.org/10.1038/s41594-020-00513-1
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