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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Polo, S. E. & Almouzni, G. Chromatin dynamics after DNA damage: the legacy of the access-repair-restore model. DNA Repair (Amst.) 36, 114–121 (2015).
House, N. C. M., Koch, M. R. & Freudenreich, C. H. Chromatin modifications and DNA repair: beyond double-strand breaks. Front. Genet. 5, 296 (2014).
Herbette, M. et al. The C. elegans SET-2/SET1 histone H3 Lys4 (H3K4) methyltransferase preserves genome stability in the germline. DNA Repair (Amst.) 57, 139–150 (2017).
Li, T. & Kelly, W. G. A role for Set1/MLL-related components in epigenetic regulation of the Caenorhabditis elegans germ line. PLoS Genet. 7, e1001349 (2011).
Fisher, K., Southall, S. M., Wilson, J. R. & Poulin, G. B. Methylation and demethylation activities of a C. elegans MLL-like complex attenuate RAS signalling. Dev. Biol. 341, 142–153 (2010).
Xiao, Y. et al. Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys4 methylation in embryos and adult germ cells. Proc. Natl Acad. Sci. USA 108, 8305–8310 (2011).
Simonet, T., Dulermo, R., Schott, S. & Palladino, F. Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Dev. Biol. 312, 367–383 (2007).
Qu, Q. et al. Structure and conformational dynamics of a COMPASS histone H3K4 methyltransferase complex. Cell 174, 1117–1126 (2018).
Takahashi, Y. H. et al. Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human. Proc. Natl Acad. Sci. USA 108, 20526–20531 (2011).
Patel, A., Vought, V. E., Dharmarajan, V. & Cosgrove, M. S. A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J. Biol. Chem. 286, 3359–3369 (2011).
Greer, E. L. et al. A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Rep. 7, 113–126 (2014).
Katz, D. J., Edwards, T. M., Reinke, V. & Kelly, W. G. A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory. Cell 137, 308–320 (2009).
Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri- and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 (2007).
Nottke, A. C. et al. SPR-5 is a histone H3K4 demethylase with a role in meiotic double-strand break repair. Proc. Natl Acad. Sci. USA 108, 12805–12810 (2011).
Greer, E. L., Becker, B., Latza, C., Antebi, A. & Shi, Y. Mutation of C. elegans demethylase spr-5 extends transgenerational longevity. Cell Res. 26, 229–238 (2016).
Mosammaparast, N. et al. The histone demethylase LSD1/KDM1A promotes the DNA damage response. J. Cell Biol. 203, 457–470 (2013).
Faucher, D. & Wellinger, R. J. Methylated H3K4, a transcription-associated histone modification, is involved in the DNA damage response pathway. PLoS Genet. 6, e1001082 (2010).
Svejstrup, J. Q. Mechanisms of transcription-coupled DNA repair. Nat. Rev. Mol. Cell Biol. 3, 21–29 (2002).
Bohr, V. A., Smith, C. A., Okumoto, D. S. & Hanawalt, P. C. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell 40, 359–369 (1985).
Epanchintsev, A. et al. Cockayne’s syndrome A and B proteins regulate transcription arrest after genotoxic stress by promoting ATF3 degradation. Mol. Cell 68, 1054–1066 (2017).
Edifizi, D. & Schumacher, B. Genome instability in development and aging: insights from nucleotide excision repair in humans, mice and worms. Biomolecules 5, 1855–1869 (2015).
Babu, V., Hofmann, K. & Schumacher, B. A C. elegans homolog of the Cockayne syndrome complementation group A gene. DNA Repair (Amst.) 24, 57–62 (2014).
Mueller, M. M. et al. DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat. Cell Biol. 16, 1168–1179 (2014).
Greer, E. L. et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387 (2010).
Wang, S., Fisher, K. & Poulin, G. B. Lineage specific trimethylation of H3 on lysine 4 during C. elegans early embryogenesis. Dev. Biol. 355, 227–238 (2011).
Engert, C. G., Droste, R., van Oudenaarden, A. & Horvitz, H. R. A Caenorhabditis elegans protein with a PRDM9-like SET domain localizes to chromatin-associated foci and promotes spermatocyte gene expression, sperm production and fertility. PLoS Genet. 14, e1007295 (2018).
Ermolaeva, M. A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013).
Greer, E. L. et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371 (2011).
Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).
Herz, H. M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604–2620 (2012).
Ou, H.-L., Kim, C. S., Uszkoreit, S., Wickström, S. A. & Schumacher, B. Somatic niche cells regulate the CEP-1/p53-mediated DNA damage response in primordial germ cells. Dev. Cell 50, 167–183 (2019).
Celniker, S. E. et al. Unlocking the secrets of the genome. Nature 459, 927–930 (2009).
Liu, T. et al. Broad chromosomal domains of histone modification patterns in C. elegans. Genome Res. 21, 227–236 (2011).
Soares, L. M. et al. Determinants of histone H3K4 methylation patterns. Mol. Cell 68, 773–785 (2017).
Kantor, G. J. & Hull, D. R. An effect of ultraviolet light on RNA and protein synthesis in nondividing human diploid fibroblasts. Biophys. J. 27, 359–370 (1979).
Edifizi, D. et al. Multilayered reprogramming in response to persistent DNA damage in C. elegans. Cell Rep. 20, 2026–2043 (2017).
Powley, I. R. et al. Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. Genes Dev. 23, 1207–1220 (2009).
Min, K. J. & Tatar, M. Restriction of amino acids extends lifespan in Drosophila melanogaster. Mech. Ageing Dev. 127, 643–646 (2006).
Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).
Schneider-Poetsch, T. et al. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6, 209–217 (2010).
Marteijn, J. A. et al. Nucleotide excision repair–induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. J. Cell Biol. 186, 835–847 (2009).
Malik, S. et al. Rad26p, a transcription-coupled repair factor, is recruited to the site of DNA lesion in an elongating RNA polymerase II-dependent manner in vivo. Nucleic Acids Res. 38, 1461–1477 (2010).
Pena, P. V. et al. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008).
Rossetto, D., Truman, A. W., Kron, S. J. & Côté, J. Epigenetic modifications in double-strand break DNA damage signaling and repair. Clin. Cancer Res. 16, 4543–4552 (2010).
Oksenych, V. et al. Histone methyltransferase DOT1L drives recovery of gene expression after a genotoxic attack. PLoS Genet. 9, e1003611 (2013).
Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
Pekowska, A., Benoukraf, T., Ferrier, P. & Spicuglia, S. A unique H3K4me2 profile marks tissue-specific gene regulation. Genome Res. 20, 1493–1502 (2010).
Wang, Y., Li, X. & Hu, H. H3K4me2 reliably defines transcription factor binding regions in different cells. Genomics 103, 222–228 (2014).
Le May, N. et al. NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. Mol. Cell 38, 54–66 (2010).
Lee, J. H. et al. Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging. Nucleic Acids Res. 47, 8548–8562 (2019).
Foltánková, V., Legartová, S., Kozubek, S., Hofer, M. & Bártová, E. DNA-damage response in chromatin of ribosomal genes and the surrounding genome. Gene 522, 156–167 (2013).
Aho, E. R. et al. Displacement of WDR5 from chromatin by a WIN site inhibitor with picomolar affinity. Cell Rep. 26, 2916–2928 (2019).
Muthusamy, V. & Piva, T. J. The UV response of the skin: a review of the MAPK, NFκB and TNFα signal transduction pathways. Arch. Dermatol. Res. 302, 5–17 (2010).
Gout, J. F. et al. The landscape of transcription errors in eukaryotic cells. Sci. Adv. 3, e1701484 (2017).
Anisimova, A. S., Alexandrov, A. I., Makarova, N. E., Gladyshev, V. N. & Dmitriev, S. E. Protein synthesis and quality control in aging. Aging (Albany NY) 10, 4269–4288 (2018).
Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).
Takauji, Y. et al. Restriction of protein synthesis abolishes senescence features at cellular and organismal levels. Sci. Rep. 6, 18722 (2016).
Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061–1064 (2009).
Silvera, D. et al. mTORC1 and -2 coordinate transcriptional and translational reprogramming in resistance to DNA damage and replicative stress in breast cancer cells. Mol. Cell Biol. 37, e00577–16 (2017).
Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
Wagle, P., Nikolić, M. & Frommolt, P. QuickNGS elevates next-generation sequencing data analysis to a new level of automation. BMC Genomics 16, 487 (2015).
Larance, M. et al. Stable-isotope labeling with amino acids in nematodes. Nat. Methods 8, 849–851 (2011).
Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47, D442–D450 (2019).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
Allhoff, M., Seré, K., Pires, J. F., Zenke, M. & Costa, I. G. Differential peak calling of ChIP-seq signals with replicates with THOR. Nucleic Acids Res. 44, e153 (2016).
Kondili, M. et al. UROPA: a tool for Universal RObust Peak Annotation. Sci. Rep. 7, 2593 (2017).
Subhash, S. & Kanduri, C. GeneSCF: a real-time based functional enrichment tool with support for multiple organisms. BMC Bioinformatics 17, 365 (2016).
Szklarczyk, D. et al. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607–D613 (2019).
Ramírez, F., Dündar, F., Diehl, S., Grüning, B. A. & Manke, T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).
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).
The authors declare no competing interests.
Peer review information Beth Moorefield was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–6.
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.
List of genes that have changes in H3K4me2 deposition (ChIP–seq), transcription (RNA-seq) and proteomics (isotope labeling assay).
Uncropped western blot images.
Statistical source data for graphs in this paper.
About this article
Cite this article
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
Journal of Investigative Dermatology (2021)
Nature Communications (2021)
A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value