Multilayered Reprogramming in Response to Persistent DNA Damage in C. elegans

Abstract

SummaryDNA 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.

The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury

“…CR ameliorated cisplatin-induced damage to an extent that made kidneys of these animals almost indistinguishable from healthy vehicle treated controls. One exception was the finding that kidneys from calorically restricted mice had a higher abundance of proteins promoting fatty acid synthesisa metabolic pathway that has interestingly already been linked to stress resistance in other models such as nematodes [36][37][38] . Analysis of glycerophospholipids revealed a loss of membrane lipids due to cisplatin treatment that is lower after CR.…”

Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging

“…Technological advances in mass-spectrometry (MS)-based approaches have made large-scale protein as well as lipid and metabolite quantification accessible and usable for a growing community of scientists across various fields of the life sciences [ 20 ]. Such approaches, applied to different model organisms and coupled to global transcriptome studies [ 21 , 22 , 23 ], are recently emerging to provide insights into the global protein dynamics and alterations in the carbohydrate, amino acid, and lipid metabolism during the physiological adaptations to stress [ 10 , 15 , 19 , 24 ], as well as during aging [ 17 , 25 , 26 ] ( Figure 1 and Table 1 ).…”

“…The nematode Caenorhabditis elegans is a versatile metazoan model organism to perform similar coupled omics and bioinformatics in vivo studies. Upon different conditions of heat, osmotic, and oxidative-stress [ 16 , 19 ], or after genotoxic UV-treatment in a background of NER deficiencies [ 10 ], many of the major cellular processes, such as chromatin remodeling, protein homeostasis and lipid metabolism were affected ( Table 1 ). These stress response mechanisms, coupled to organismal metabolic changes, were also found to be similarly regulated in the nematode during aging [ 17 , 18 , 31 ], suggesting an active role of stresses and DNA damage accumulation in the physiological adaptations manifested in aged animals.…”

“…Transcriptome and proteome studies in C. elegans , have also contributed to the identification of the key regulators of stress responses [ 12 , 19 , 51 , 52 , 53 ] and longevity [ 10 , 17 , 31 ], with the conserved IIS pathway taking centre stage [ 17 , 54 , 55 , 56 , 57 ]. Similar to the somatotropic attenuation observed in NER mutant mice, in NER deficient C. elegans, the transcription factor DAF-16/FOXO, which is activated when IIS is attenuated, overcomes the developmental delay and elevates the tolerance to unrepaired DNA lesions [ 12 , 49 , 58 ].…”

“…The pathological consequences of unrepaired DNA damage are complex and so is the cellular DNA damage response that orchestrates physiological adaptations [ 10 ] ranging from the modulation of signalling pathways [ 11 , 12 , 13 , 14 ] to metabolic adjustments [ 15 , 16 ]. Interestingly, similar adaptations have been observed during aging [ 17 , 18 ] and upon stress conditions [ 19 ], suggesting that the aging organism responds to the accumulation of DNA lesions over time.…”