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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.

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Related in: MedlinePlus

NER deficiency does not affect normal life span but loss of ercc-1 and xpf-1 enhances long life span of daf-2 mutants. (a and b) show the fraction of live adult animals with and without mutations in (a) wild type (n=331), xpa-1 (n=81), csb-1 (n=85), xpa-1;csb-1 (n=71), ercc-1 (n=177), xpf-1(e1487; n= 66), xpg-1(tm1670; n= 142). In (b) wild type (n=42), daf-2 (n=87) ercc-1; daf-2 (n= 86), xpf-1; daf-2 (n=83). Mean life span of at least two independent experiments is depicted
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fig1: NER deficiency does not affect normal life span but loss of ercc-1 and xpf-1 enhances long life span of daf-2 mutants. (a and b) show the fraction of live adult animals with and without mutations in (a) wild type (n=331), xpa-1 (n=81), csb-1 (n=85), xpa-1;csb-1 (n=71), ercc-1 (n=177), xpf-1(e1487; n= 66), xpg-1(tm1670; n= 142). In (b) wild type (n=42), daf-2 (n=87) ercc-1; daf-2 (n= 86), xpf-1; daf-2 (n=83). Mean life span of at least two independent experiments is depicted

Mentions: To understand whether DNA-repair deficiency in C. elegans is associated with a shortened life span, we measured the adult life span20 of healthy looking animals with mutated NER genes csb-1, ercc-1, xpa-1, xpf-1, xpg-1 and xpa-1;csb-1 double mutants.21 Strikingly, we did not detect decreased life span in any of the tested mutants (Figure 1a), indicating that NER is not life-span limiting in adult C. elegans.


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)

NER deficiency does not affect normal life span but loss of ercc-1 and xpf-1 enhances long life span of daf-2 mutants. (a and b) show the fraction of live adult animals with and without mutations in (a) wild type (n=331), xpa-1 (n=81), csb-1 (n=85), xpa-1;csb-1 (n=71), ercc-1 (n=177), xpf-1(e1487; n= 66), xpg-1(tm1670; n= 142). In (b) wild type (n=42), daf-2 (n=87) ercc-1; daf-2 (n= 86), xpf-1; daf-2 (n=83). Mean life span of at least two independent experiments is depicted
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: NER deficiency does not affect normal life span but loss of ercc-1 and xpf-1 enhances long life span of daf-2 mutants. (a and b) show the fraction of live adult animals with and without mutations in (a) wild type (n=331), xpa-1 (n=81), csb-1 (n=85), xpa-1;csb-1 (n=71), ercc-1 (n=177), xpf-1(e1487; n= 66), xpg-1(tm1670; n= 142). In (b) wild type (n=42), daf-2 (n=87) ercc-1; daf-2 (n= 86), xpf-1; daf-2 (n=83). Mean life span of at least two independent experiments is depicted
Mentions: To understand whether DNA-repair deficiency in C. elegans is associated with a shortened life span, we measured the adult life span20 of healthy looking animals with mutated NER genes csb-1, ercc-1, xpa-1, xpf-1, xpg-1 and xpa-1;csb-1 double mutants.21 Strikingly, we did not detect decreased life span in any of the tested mutants (Figure 1a), indicating that NER is not life-span limiting in adult C. elegans.

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