Nucleotide Excision Repair (NER) is a versatile DNA repair pathway that removes a wide variety of helix-distorting DNA lesions, including those induced by UV irradiation. Two subpathways in NER can be discerned, one which detects DNA damage anywhere in the genome, called global genome NER (GG-NER), and one which detects damage in the transcribed strand during transcription, called transcription-coupled NER (TC-NER). Following detection, the damaged DNA strand is excised and the resulting gap is repaired by novel DNA synthesis. In humans, NER-deficiency is associated with severe clinical disorders characterized by cancer predisposition and/or pleiotropic developmental defects and accelerated aging of which the pathogenesis is only partially understood.
We use C. elegans to understand the in vivo impact of DNA damage and the biological relevance of NER in a multicellular, developing organism. Previously, we showed that UV-exposed germ cells mainly depend on functional GG-NER, while postembryonic cells predominantly depend on TC-NER. Further analysis of development and aging associated with NER deficiency shows that, contrary to expectation, DNA damage accumulation does not decrease adult lifespan of post-mitotic tissue. Surprisingly, NER deficiency even further extends life-span of long-lived
daf-2 mutants, through an adaptive activation of stress signaling. Contrary, NER deficiency leads to a striking decrease in replicative lifespan and transgenerational aging of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced when additional DNA repair pathways besides NER are impaired. These results show that different DNA lesions contribute to replicative aging and suggest that also in patients there might be a direct link between symptoms and the level of DNA repair deficiency.