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-, ercc-1-, xpf-1- and xpg-1-deficient animals accumulate RAD-51 foci. RAD-51 foci visualized by the immunofluorescence of gonads of wild-type, xpa-1, ercc-1, xpf-1 and xpg-1 animals. Shown is the distal part of the gonad containing proliferating germ cells prior to meiosis. For each strain, two examples are shown (left and right panels). The panels on the right show a higher magnification of the distal gonad. The bar in the first image represents 50 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: xpa-1-, ercc-1-, xpf-1- and xpg-1-deficient animals accumulate RAD-51 foci. RAD-51 foci visualized by the immunofluorescence of gonads of wild-type, xpa-1, ercc-1, xpf-1 and xpg-1 animals. Shown is the distal part of the gonad containing proliferating germ cells prior to meiosis. For each strain, two examples are shown (left and right panels). The panels on the right show a higher magnification of the distal gonad. The bar in the first image represents 50 μm

Mentions: Thus far, we have assumed that DNA damage accumulated in the DNA-repair mutants, which is supported by the increased mutational rate in xpa-1 C. elegans22 and XPA- and ERCC1-deficient mice.29 To test whether DNA damage load is indeed higher in these mutants, we determined RAD-51 foci formation in proliferating germ cells. These foci arise after replication stress from various forms of DNA damage.30 We observed more RAD-51 foci in mitotic germ cells of xpa-1 mutant animals compared with wild-type animals, which was further increased in ercc-1, xpf-1 and xpg-1 mutants (Figure 5). We therefore hypothesize that spontaneously occurring DNA damage does indeed accumulate in these mutants and presume that this leads to the observed phenotypic defects and changes in gene expression.


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-, ercc-1-, xpf-1- and xpg-1-deficient animals accumulate RAD-51 foci. RAD-51 foci visualized by the immunofluorescence of gonads of wild-type, xpa-1, ercc-1, xpf-1 and xpg-1 animals. Shown is the distal part of the gonad containing proliferating germ cells prior to meiosis. For each strain, two examples are shown (left and right panels). The panels on the right show a higher magnification of the distal gonad. The bar in the first image represents 50 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: xpa-1-, ercc-1-, xpf-1- and xpg-1-deficient animals accumulate RAD-51 foci. RAD-51 foci visualized by the immunofluorescence of gonads of wild-type, xpa-1, ercc-1, xpf-1 and xpg-1 animals. Shown is the distal part of the gonad containing proliferating germ cells prior to meiosis. For each strain, two examples are shown (left and right panels). The panels on the right show a higher magnification of the distal gonad. The bar in the first image represents 50 μm
Mentions: Thus far, we have assumed that DNA damage accumulated in the DNA-repair mutants, which is supported by the increased mutational rate in xpa-1 C. elegans22 and XPA- and ERCC1-deficient mice.29 To test whether DNA damage load is indeed higher in these mutants, we determined RAD-51 foci formation in proliferating germ cells. These foci arise after replication stress from various forms of DNA damage.30 We observed more RAD-51 foci in mitotic germ cells of xpa-1 mutant animals compared with wild-type animals, which was further increased in ercc-1, xpf-1 and xpg-1 mutants (Figure 5). We therefore hypothesize that spontaneously occurring DNA damage does indeed accumulate in these mutants and presume that this leads to the observed phenotypic defects and changes in gene expression.

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