Global Genome Responses to DNA-Repair Deficiency Modulate Aging and Stress Response Pathways

Abstract

The genomes of all animals are constantly challenged by exogenous and endogenous sources of DNA damaging agents. UV radiation, chemicals, pollutants, and by-products of the cells’ own metabolism may damage the genetic material. Such damages are harmful to the animal as they may cause mutations or generate cytotoxic lesions, which in turn may lead to disease, cancer and aging. Protection of the genome is therefore of the utmost importance. To counteract such potential detrimental effects, all organisms have developed protective mechanisms such as antioxidants and DNA repair mechanisms. DNA excision repair proteins detect lesions in DNA, excise the damaged base and re-insert a correct base, thus maintaining the correct coding properties of the genome. Defects in DNA repair mechanisms may lead to cancer, neurodegeneration, other age-related pathologies or senescence. The nematode Caenorhabditis elegans (C. elegans) contains very few DNA glycosylases, which are the lesion-detecting proteins in DNA excision repair, compared to other animals and organisms. Analysis of all transcribed genes in DNA repair-deficient mutants in C. elegans revealed a global transcriptional response aimed at minimizing further damage to the genome. This involved a down-regulation of insulin-like signaling and an upregulation of antioxidants and stress response genes, similar to the response seen in both long-lived and old animals. This response seems to be conserved across different species as analysis of comparable mutants in the yeast Saccharomyces cerevisiae and mouse showed a similar response. Pathway reconstruction and literature mining suggests that this response is not elicited only by lack of repair per se, but rather from aberrant or attempted processing of lesions by other repair pathways than those normally repairing such lesions. This result in lesions that block the transcription of active genes and signal the transcription of other genes aimed at reducing further damage to DNA. Analysis of C. elegans mutants deficient in two different repair pathways revealed a completely different response with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as downregulation of other DNA repair pathways. The mechanism and signaling origin of this response is yet unknown. Gene expression profiling is emerging as a powerful complementary tool to classical genetics and molecular analysis. By taking a systems biology approach, which takes into account the interplay between many pathways, gene expression profiling may aid in the interpretation of observed phenotypes and assist in the generation of new testable hypotheses.