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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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DNA damage sensitivities of xpa-1, ercc-1, xpf-1 and xpg-1 mutants. (a and b) show the mean survival of mutant animals following exposure to γ-irradiation. (c) shows the mean survival upon exposure to nitrogen mustard. ercc-1 and xpf-1 animals are strongly hypersensitive to DNA damage induced by UV irradiation (Supplementary Figure S2),12 ionizing radiation and nitrogen mustard. xpg-1 animals are strongly hypersensitive to UV and ionizing radiation, whereas xpa-1 animals are only strongly hypersensitive to UV irradiation.12 Assays were performed at least two times and on independent occasions. Data for xpf-1 and ercc-1 were normalized because untreated mutants already show some embryonic lethality. Error bars denote s.e.m. Asterisks indicate significant differences compared with wild type (P=0.05)
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fig6: DNA damage sensitivities of xpa-1, ercc-1, xpf-1 and xpg-1 mutants. (a and b) show the mean survival of mutant animals following exposure to γ-irradiation. (c) shows the mean survival upon exposure to nitrogen mustard. ercc-1 and xpf-1 animals are strongly hypersensitive to DNA damage induced by UV irradiation (Supplementary Figure S2),12 ionizing radiation and nitrogen mustard. xpg-1 animals are strongly hypersensitive to UV and ionizing radiation, whereas xpa-1 animals are only strongly hypersensitive to UV irradiation.12 Assays were performed at least two times and on independent occasions. Data for xpf-1 and ercc-1 were normalized because untreated mutants already show some embryonic lethality. Error bars denote s.e.m. Asterisks indicate significant differences compared with wild type (P=0.05)

Mentions: Survival assays showed that ercc-1, xpf-1 and xpg-1 animals were hypersensitive to γ-rays, which mainly induce oxidative DNA damage and strand breaks,38 whereas xpa-1 animals were only marginally sensitive (Figures 6a and b). Additionally, ercc-1 and xpf-1, but not xpa-1 and xpg-1, animals showed hypersensitivity to nitrogen mustard (HN2), which induces monoadducts and ICLs38 (Figure 6c). These results confirm that ERCC-1, XPF-1 and XPG-1 function in different pathways, whereas XPA-1 appears more NER-specific. Importantly, these results likely explain why there is more DNA damage accumulation and consequently a stronger replicative decline in mutants defective in these multifunctional endonucleases, compared with xpa-1.


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)

DNA damage sensitivities of xpa-1, ercc-1, xpf-1 and xpg-1 mutants. (a and b) show the mean survival of mutant animals following exposure to γ-irradiation. (c) shows the mean survival upon exposure to nitrogen mustard. ercc-1 and xpf-1 animals are strongly hypersensitive to DNA damage induced by UV irradiation (Supplementary Figure S2),12 ionizing radiation and nitrogen mustard. xpg-1 animals are strongly hypersensitive to UV and ionizing radiation, whereas xpa-1 animals are only strongly hypersensitive to UV irradiation.12 Assays were performed at least two times and on independent occasions. Data for xpf-1 and ercc-1 were normalized because untreated mutants already show some embryonic lethality. Error bars denote s.e.m. Asterisks indicate significant differences compared with wild type (P=0.05)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: DNA damage sensitivities of xpa-1, ercc-1, xpf-1 and xpg-1 mutants. (a and b) show the mean survival of mutant animals following exposure to γ-irradiation. (c) shows the mean survival upon exposure to nitrogen mustard. ercc-1 and xpf-1 animals are strongly hypersensitive to DNA damage induced by UV irradiation (Supplementary Figure S2),12 ionizing radiation and nitrogen mustard. xpg-1 animals are strongly hypersensitive to UV and ionizing radiation, whereas xpa-1 animals are only strongly hypersensitive to UV irradiation.12 Assays were performed at least two times and on independent occasions. Data for xpf-1 and ercc-1 were normalized because untreated mutants already show some embryonic lethality. Error bars denote s.e.m. Asterisks indicate significant differences compared with wild type (P=0.05)
Mentions: Survival assays showed that ercc-1, xpf-1 and xpg-1 animals were hypersensitive to γ-rays, which mainly induce oxidative DNA damage and strand breaks,38 whereas xpa-1 animals were only marginally sensitive (Figures 6a and b). Additionally, ercc-1 and xpf-1, but not xpa-1 and xpg-1, animals showed hypersensitivity to nitrogen mustard (HN2), which induces monoadducts and ICLs38 (Figure 6c). These results confirm that ERCC-1, XPF-1 and XPG-1 function in different pathways, whereas XPA-1 appears more NER-specific. Importantly, these results likely explain why there is more DNA damage accumulation and consequently a stronger replicative decline in mutants defective in these multifunctional endonucleases, compared with xpa-1.

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