title: DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.
abstract: Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.
authors.affiliation: Department of Genetics, Biomedical Science, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: H
authors.identifier: 0000000344175358
authors.initials: H
authors.lastname: Lans
authors.forename: J M
authors.initials: JM
authors.lastname: Lindvall
authors.forename: K
authors.initials: K
authors.lastname: Thijssen
authors.forename: A E
authors.initials: AE
authors.lastname: Karambelas
authors.forename: D
authors.initials: D
authors.lastname: Cupac
authors.forename: O
authors.initials: O
authors.lastname: Fensgård
authors.forename: G
authors.initials: G
authors.lastname: Jansen
authors.forename: J H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: H
authors.initials: H
authors.lastname: Nilsen
authors.forename: W
authors.initials: W
authors.lastname: Vermeulen
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D008136:Longevity / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D025341:Principal Component Analysis; D013312:Stress, Physiological
chemical_list: D029742:Caenorhabditis elegans Proteins