DNA damage responses have been well characterized in their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence, and apoptosis 1. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult C. elegans worms germ cells undergo mitotic and meiotic cell divisions while somatic tissues are entirely postmitotic. Consequently, DNA damage checkpoints function specifically in the germline 2, whereas somatic tissues in adult C. elegans are highly radio-resistant 3. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells 4. 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.
The demographic shift in the human population reflects an aging society-over 20% of Europeans are predicted to be 65 or over by the year 2025 (Riera & Dillin, 2015). Aging is the major risk factor for developing chronic diseases, such as cancer, Alzheimer's disease, and cardiovascular complications (Partridge et al., 2018).Unfortunately, humans spend on average one-fifth of their lifetime in poor health suffering from one or multiple age-related chronic diseases (Partridge et al., 2018). However, the onset of age-related pathologies is not fixed, and the rate of aging was shown to be malleable. The goal of biomedical research on aging or geroscience is to identify interventions that compress late-life morbidity to increase the period spent healthy and free from disease.
The maintenance of the genome is of pivotal importance for the functional integrity of cells and tissues. The gradual accumulation of DNA damage is thought to contribute to the functional decline of tissues and organs with ageing. Defects in multiple genome maintenance systems cause human disorders characterized by cancer susceptibility, developmental failure, and premature ageing. The complex pathological consequences of genome instability are insufficiently explained by cell-autonomous DNA damage responses (DDR) alone. Quality control pathways play an important role in DNA repair and cellular DDR pathways. Recent years have revealed non-cell autonomous effects of DNA damage that impact the physiological adaptations during ageing. We will discuss the role of quality assurance pathways in cell-autonomous and systemic responses to genome instability.
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