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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

ercc-1, xpg-1 and xpg-1 deficiency leads to developmental and growth defects. (a) depicts Nomarski images of a typical young adult wild-type animal and examples of similar age ercc-1, xpg-1 and xpf-1 animals that show growth and developmental defects. Images were taken with the same magnification. Bar in the first image represents 50 μm. (b) shows examples of similar-age normal (wild-type) and morphologically abnormal (ercc-1 and xpg-1) gonad/uterus areas. In the ercc-1 mutant, no healthy oocytes (white arrow) can be discerned in the proximal part of the gonad, whereas in the xpg-1 mutant, oocytes are present but the distal part of the gonad (arrowhead) is mislocalized. The bar in the first image represents 50 μm. (c) depicts the quantification of the growth of different mutants by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C
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fig3: ercc-1, xpg-1 and xpg-1 deficiency leads to developmental and growth defects. (a) depicts Nomarski images of a typical young adult wild-type animal and examples of similar age ercc-1, xpg-1 and xpf-1 animals that show growth and developmental defects. Images were taken with the same magnification. Bar in the first image represents 50 μm. (b) shows examples of similar-age normal (wild-type) and morphologically abnormal (ercc-1 and xpg-1) gonad/uterus areas. In the ercc-1 mutant, no healthy oocytes (white arrow) can be discerned in the proximal part of the gonad, whereas in the xpg-1 mutant, oocytes are present but the distal part of the gonad (arrowhead) is mislocalized. The bar in the first image represents 50 μm. (c) depicts the quantification of the growth of different mutants by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C

Mentions: Consistent with the transcriptomic prominence of BPs related to growth and development, we noticed that a fraction of the population of ercc-1, xpf-1 and xpg-1 mutants displayed developmental and growth defects (Figures 3a and b and Table 1). To quantify this, we measured developmental speed of animals laid as eggs over ∼70 h at 20 °C, during which time all wild-type animals reached adulthood (Figure 3c). In contrast, around 20% of ercc-1/xpf-1 mutants failed to reach adulthood in this time period (Figure 3c). Similar defects were observed in another xpf-1 loss-of-function allelic variant (tm2842), which has not been described before but displays UV hypersensitivity that is similar to that of the xpf-1(e1487) mutant12 (Supplementary Figure S2). Furthermore, a comparable developmental delay was observed in two xpg-1 mutant strains (Figure 3c). Growth-retarded animals showed pleiotropic defects (Figures 3a and b). Some animals became adults at a later time point and laid eggs normally, whereas others produced inviable eggs or no eggs at all, or were arrested in development and never reached adulthood. A smaller but noteworthy proportion of xpa-1 animals were also growth-impaired (Figure 3c). This was also observed for xpc-1; csb-1 double mutants, which show a UV sensitivity that is similar to that of the xpa-1 animals, but not in xpc-1 or csb-1 single mutants, which are less UV-sensitive.12 These observations hint at a correlation between the severity of the phenotype and the severity of the DNA-repair deficiency and suggest that DNA-repair-deficient animals are arrested in development or develop slowly if unrepaired, spontaneous DNA damage interferes with genome function.


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)

ercc-1, xpg-1 and xpg-1 deficiency leads to developmental and growth defects. (a) depicts Nomarski images of a typical young adult wild-type animal and examples of similar age ercc-1, xpg-1 and xpf-1 animals that show growth and developmental defects. Images were taken with the same magnification. Bar in the first image represents 50 μm. (b) shows examples of similar-age normal (wild-type) and morphologically abnormal (ercc-1 and xpg-1) gonad/uterus areas. In the ercc-1 mutant, no healthy oocytes (white arrow) can be discerned in the proximal part of the gonad, whereas in the xpg-1 mutant, oocytes are present but the distal part of the gonad (arrowhead) is mislocalized. The bar in the first image represents 50 μm. (c) depicts the quantification of the growth of different mutants by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: ercc-1, xpg-1 and xpg-1 deficiency leads to developmental and growth defects. (a) depicts Nomarski images of a typical young adult wild-type animal and examples of similar age ercc-1, xpg-1 and xpf-1 animals that show growth and developmental defects. Images were taken with the same magnification. Bar in the first image represents 50 μm. (b) shows examples of similar-age normal (wild-type) and morphologically abnormal (ercc-1 and xpg-1) gonad/uterus areas. In the ercc-1 mutant, no healthy oocytes (white arrow) can be discerned in the proximal part of the gonad, whereas in the xpg-1 mutant, oocytes are present but the distal part of the gonad (arrowhead) is mislocalized. The bar in the first image represents 50 μm. (c) depicts the quantification of the growth of different mutants by counting the larval and adult stages that are observed ∼70 h after animals are laid as eggs at 20 °C
Mentions: Consistent with the transcriptomic prominence of BPs related to growth and development, we noticed that a fraction of the population of ercc-1, xpf-1 and xpg-1 mutants displayed developmental and growth defects (Figures 3a and b and Table 1). To quantify this, we measured developmental speed of animals laid as eggs over ∼70 h at 20 °C, during which time all wild-type animals reached adulthood (Figure 3c). In contrast, around 20% of ercc-1/xpf-1 mutants failed to reach adulthood in this time period (Figure 3c). Similar defects were observed in another xpf-1 loss-of-function allelic variant (tm2842), which has not been described before but displays UV hypersensitivity that is similar to that of the xpf-1(e1487) mutant12 (Supplementary Figure S2). Furthermore, a comparable developmental delay was observed in two xpg-1 mutant strains (Figure 3c). Growth-retarded animals showed pleiotropic defects (Figures 3a and b). Some animals became adults at a later time point and laid eggs normally, whereas others produced inviable eggs or no eggs at all, or were arrested in development and never reached adulthood. A smaller but noteworthy proportion of xpa-1 animals were also growth-impaired (Figure 3c). This was also observed for xpc-1; csb-1 double mutants, which show a UV sensitivity that is similar to that of the xpa-1 animals, but not in xpc-1 or csb-1 single mutants, which are less UV-sensitive.12 These observations hint at a correlation between the severity of the phenotype and the severity of the DNA-repair deficiency and suggest that DNA-repair-deficient animals are arrested in development or develop slowly if unrepaired, spontaneous DNA damage interferes with genome function.

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