Multilayered Reprogramming in Response to Persistent DNA Damage in C. elegans
| Autor: | Laia Castells-Roca, Susanne Brodesser, Vipin Babu, Michael M. Mueller, Björn Schumacher, Marcus Krüger, Diletta Edifizi, Hendrik Nolte |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability Proteomics Aging DNA Repair Proteome DNA repair DNA damage Ultraviolet Rays Active Transport Cell Nucleus Down-Regulation Biology medicine.disease_cause DNA damage response Synaptic Transmission General Biochemistry Genetics and Molecular Biology Article Transcriptome 03 medical and health sciences 0302 clinical medicine medicine Animals Caenorhabditis elegans Caenorhabditis elegans Proteins lcsh:QH301-705.5 Gene 2. Zero hunger Genetics Cell Nucleus Mutation Ion Transport Cellular Reprogramming Lipid Metabolism Phosphoproteins nucleotide excision repair 3. Good health Up-Regulation 030104 developmental biology lcsh:Biology (General) Starvation Proteolysis lipidomics Reprogramming 030217 neurology & neurosurgery Nucleotide excision repair DNA Damage |
| Zdroj: | Cell Reports Cell Reports, Vol 20, Iss 9, Pp 2026-2043 (2017) |
| ISSN: | 2211-1247 |
| Popis: | Summary DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis elegans lead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated proteostatic response. We assign central roles for the insulin-, EGF-, and AMPK-like signaling pathways in orchestrating the adaptive response to DNA damage. Our results provide insights into the DNA damage responses in the organismal context. Graphical Abstract Highlights • Proteome responses to persistent DNA damage correlate with starvation and aging • Proteostatic shift reduces ubiquitin proteasome and chaperones and relies on autophagy • Metabolic adaptations to DNA damage reduce fatty acid synthesis • Insulin-, EGF-, and AMPK-like signaling pathways respond to UV-induced DNA damage Edifizi et al. provide a comprehensive proteomics, phosphoproteomics, and lipidomics analysis of the response to persistent DNA damage in a metazoan organism. Proteostasis shifts toward autophagy, fatty acid metabolism is attenuated, and the insulin-, EGF-, and AMPK-like signaling pathways form the center of the response network. |
| Databáze: | OpenAIRE |
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