Limits...
DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.

Lans H, Lindvall JM, Thijssen K, Karambelas AE, Cupac D, Fensgård O, Jansen G, Hoeijmakers JH, Nilsen H, Vermeulen W - Cell Death Differ. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biomedical Science, Erasmus MC, Rotterdam, The Netherlands.

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.

Show MeSH

Related in: MedlinePlus

xpa-1; brc-1 double mutants show enhanced developmental and replicative capacity defects. (a) depicts a quantification of the growth of wild-type, xpa-1 and brc-1 single and double mutants, by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C. (b) Shown is the transgenerational replicative capacity of xpa-1, brc-1 and xpa-1; brc-1 mutants. The cumulative results of two independent experiments at 25 °C are depicted
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824592&req=5

fig7: xpa-1; brc-1 double mutants show enhanced developmental and replicative capacity defects. (a) depicts a quantification of the growth of wild-type, xpa-1 and brc-1 single and double mutants, by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C. (b) Shown is the transgenerational replicative capacity of xpa-1, brc-1 and xpa-1; brc-1 mutants. The cumulative results of two independent experiments at 25 °C are depicted

Mentions: To test the notion that defects in more than one repair pathway lead to stronger developmental and transgenerational replicative failure, we crossed xpa-1 with brc-1 mutants. BRC-1 is orthologous to mammalian BRCA1 and functions in DSB repair through inter-sister meiotic recombination in C. elegans.39 Importantly, brc-1 mutants are hypersensitive to ionizing radiation and ICL-inducing agents, but not to UV irradiation (Supplementary Figure S4)30, 40 and thus resemble ercc-1/xpf-1 mutants except for UV hypersensitivity. Growth and transgenerational replicative capacity were strongly reduced in xpa-1; brc-1 double mutants, compared with their single-mutant counterparts (Figure 7 and Supplementary Figure S5). These results strongly support the hypothesis that the severe defects in ercc-1, xpf-1 and xpg-1 mutants are caused by impairment of multiple DNA-repair pathways, suggesting that these pathways collectively protect against proliferative decline induced by accumulating DNA damage in the population.


DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.

Lans H, Lindvall JM, Thijssen K, Karambelas AE, Cupac D, Fensgård O, Jansen G, Hoeijmakers JH, Nilsen H, Vermeulen W - Cell Death Differ. (2013)

xpa-1; brc-1 double mutants show enhanced developmental and replicative capacity defects. (a) depicts a quantification of the growth of wild-type, xpa-1 and brc-1 single and double mutants, by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C. (b) Shown is the transgenerational replicative capacity of xpa-1, brc-1 and xpa-1; brc-1 mutants. The cumulative results of two independent experiments at 25 °C are depicted
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824592&req=5

fig7: xpa-1; brc-1 double mutants show enhanced developmental and replicative capacity defects. (a) depicts a quantification of the growth of wild-type, xpa-1 and brc-1 single and double mutants, by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C. (b) Shown is the transgenerational replicative capacity of xpa-1, brc-1 and xpa-1; brc-1 mutants. The cumulative results of two independent experiments at 25 °C are depicted
Mentions: To test the notion that defects in more than one repair pathway lead to stronger developmental and transgenerational replicative failure, we crossed xpa-1 with brc-1 mutants. BRC-1 is orthologous to mammalian BRCA1 and functions in DSB repair through inter-sister meiotic recombination in C. elegans.39 Importantly, brc-1 mutants are hypersensitive to ionizing radiation and ICL-inducing agents, but not to UV irradiation (Supplementary Figure S4)30, 40 and thus resemble ercc-1/xpf-1 mutants except for UV hypersensitivity. Growth and transgenerational replicative capacity were strongly reduced in xpa-1; brc-1 double mutants, compared with their single-mutant counterparts (Figure 7 and Supplementary Figure S5). These results strongly support the hypothesis that the severe defects in ercc-1, xpf-1 and xpg-1 mutants are caused by impairment of multiple DNA-repair pathways, suggesting that these pathways collectively protect against proliferative decline induced by accumulating DNA damage in the population.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biomedical Science, Erasmus MC, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus