Checkpoint silencing during the DNA damage response in <i>Caenorhabditis elegans</i> embryos

Holway, Antonia H.; Kim, Seunghwan; Volpe, Adriana La; Michael, W. Matthew

doi:10.1083/jcb.200512136

Cited by 81 publications

(84 citation statements)

References 40 publications

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“…This is consistent with a previous study that found that nonhomologous end-joining is important in non-cycling somatic cells [13]. While our experiments cannot distinguish between germs cells and early embryos, such experiments would be interesting given the fact that cell cycle checkpoint activation is silenced in C. elegans in early embryos, but not in the germline [12]. Importantly, we previously showed that there was no detectable difference in UVC damage repair kinetics between wild-type and glp-1 nematodes when measured in starved L1s, prior to germ cell proliferation [23].…”

Section: Discussionsupporting

confidence: 92%

Nucleotide excision repair genes are expressed at low levels and are not detectably inducible in Caenorhabditis elegans somatic tissues, but their function is required for normal adult life after UVC exposure

Boyd

Crocker

Rodrı́guez

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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We performed experiments to characterize the inducibility of nucleotide excision repair (NER) in Caenorhabditis elegans, and to examine global gene expression in NER-deficient and -proficient strains as well as germline vs. somatic tissues, with and without genotoxic stress. We also carried out experiments to elucidate the importance of NER in the adult life of C. elegans under genotoxinstressed and control conditions. Adult lifespan was not detectably different between wild-type and NER-deficient xpa-1 nematodes under control conditions. However, exposure to 6 J/m 2 /day of ultraviolet C radiation (UVC) decreased lifespan in xpa-1 nematodes more than a dose of 100 J/m 2 / day in wild-type. Similar differential sensitivities were observed for adult size and feeding. Remarkably, global gene expression was nearly identical in young adult wild-type and xpa-1 nematodes, both in control conditions and three hours after exposure to 50 J/m 2 UVC. Neither NER genes nor protein activity were detectably inducible in young adults that lacked germ cells and developing embryos (glp-1 strain). However, expression levels of dozens of NER and other DNA damage response genes were much (5 to 30-fold) lower in adults lacking germ cells and developing embryos, suggesting that somatic and post-mitotic cells have a much lower DNA repair ability. Finally, we describe a refinement of our DNA damage assay that allows damage measurement in single nematodes.

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Section: Discussionsupporting

confidence: 92%

Nucleotide excision repair genes are expressed at low levels and are not detectably inducible in Caenorhabditis elegans somatic tissues, but their function is required for normal adult life after UVC exposure

Boyd

Crocker

Rodrı́guez

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…One possibility to be explored is that KO embryos have an increased sensitivity to DNA damage, thus in many cases they do not survive up to the larval stages. This hypothesis fits with the notion that DNA-damage-induced checkpoint is silenced during early stages of embryo development (30) to ensure that cell cycle progression is not hampered by DNA damage. In the Fe65;Fe65L1 double KO mice the phenotype observed (23), mainly characterized by focal heterotopias of neurons likely due to the pial basement membrane disruption and intriguingly similar to that observed in APP;APLP1;APLP2 mice (24), is very likely due to the impairment of an unknown Fe65 function different from that responsible for the phenotype we are describing.…”

Section: Discussionsupporting

confidence: 54%

Essential Roles for Fe65, Alzheimer Amyloid Precursor-binding Protein, in the Cellular Response to DNA Damage

Minopoli

Stante

Napolitano

et al. 2007

Journal of Biological Chemistry

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Fe65 interacts with the cytosolic domain of the Alzheimer amyloid precursor protein (APP). The functions of the Fe65 are still unknown. To address this point we generated Fe65 knockout (KO) mice. These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H 2 O 2 , an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged. Accordingly, brain extracts from Fe65 KO mice, exposed to non-lethal doses of ionizing radiations, showed high levels of ␥-H2AX and p53, thus demonstrating a higher sensitivity to X-rays than wild type mice. Nuclear Fe65 is necessary to rescue the observed phenotype, and few minutes after the exposure of MEFs to DNA damaging agents, Fe65 undergoes phosphorylation in the nucleus. With a similar timing, the proteolytic processing of APP is rapidly affected by the genotoxic stress: in fact, the cleavage of the APP COOH-terminal fragments by ␥-secretase is induced soon after the exposure of cells to etoposide, in a Fe65-dependent manner. These results demonstrate that Fe65 plays an essential role in the response of the cells to DNA damage.

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“…A tendency of dose-response in the developmental delay was observed only in the early developmental stage, which might suggest that the time allowed for repair processes in the middle and late developmental stages was fixed and independent of damage level. In many organisms, including C. elegans , D. melanogaster and Xenopus laevis , early embryogenesis is characterized by rapid progression through the cell cycle [28], [29]. Adherence to the schedule during the initial stage of development (until mid-blastula) seems to be very important for survival of the embryo, and it is programmed by specific signals during development (28).…”

Section: Discussionmentioning

confidence: 99%

“…However, if DNA is damaged during embryo gastrulation (where the G2 phase has been added into cell cycles) it results in a checkpoint-dependent delay of entry into mitosis [30]. Also in the early and fast developing embryos of C. elegans DNA damage does not inhibit the cell cycle, and this has been suggested as a mechanism (TLS based) allowing the embryo to survive even when their chromosomes are highly damaged [28]. From the perspective of the radiation tolerance in tardigrades, and also from the fact that tardigrades, nematodes and arthropods belong to the protostome superclade Ecdysozoa it will be of considerable interest to investigate the developmental processes in tardigrades, in particular the checkpoint and DNA repair system.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ionizing Radiation on Embryos of the Tardigrade Milnesium cf. tardigradum at Different Stages of Development

et al. 2013

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Tardigrades represent one of the most desiccation and radiation tolerant animals on Earth, and several studies have documented their tolerance in the adult stage. Studies on tolerance during embryological stages are rare, but differential effects of desiccation and freezing on different developmental stages have been reported, as well as dose-dependent effect of gamma irradiation on tardigrade embryos. Here, we report a study evaluating the tolerance of eggs from the eutardigrade Milnesium cf. tardigradum to three doses of gamma radiation (50, 200 and 500 Gy) at the early, middle, and late stage of development. We found that embryos of the middle and late developmental stages were tolerant to all doses, while eggs in the early developmental stage were tolerant only to a dose of 50 Gy, and showed a declining survival with higher dose. We also observed a delay in development of irradiated eggs, suggesting that periods of DNA repair might have taken place after irradiation induced damage. The delay was independent of dose for eggs irradiated in the middle and late stage, possibly indicating a fixed developmental schedule for repair after induced damage. These results show that the tolerance to radiation in tardigrade eggs changes in the course of their development. The mechanisms behind this pattern are unknown, but may relate to changes in mitotic activities over the embryogenesis and/or to activation of response mechanisms to damaged DNA in the course of development.

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Checkpoint silencing during the DNA damage response in Caenorhabditis elegans embryos

Cited by 81 publications

References 40 publications

Nucleotide excision repair genes are expressed at low levels and are not detectably inducible in Caenorhabditis elegans somatic tissues, but their function is required for normal adult life after UVC exposure

Nucleotide excision repair genes are expressed at low levels and are not detectably inducible in Caenorhabditis elegans somatic tissues, but their function is required for normal adult life after UVC exposure

Essential Roles for Fe65, Alzheimer Amyloid Precursor-binding Protein, in the Cellular Response to DNA Damage

Effects of Ionizing Radiation on Embryos of the Tardigrade Milnesium cf. tardigradum at Different Stages of Development

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