Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage

Tine Skovgaard, Lene Juel Rasmussen, Birgitte Munch-Petersen

    Publikation: KonferencebidragPosterForskning

    Resumé

    Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types.

    In order to further study the interconnection between dNTP pools and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect on the dNTP pools in rho0 cells but not in rho+ cells. In the rho0 cells a 2-3 fold increase in all four deoxynucleotides is observed.

    Besides from tRNAs and mRNAs the mitochondrial genome is encoding 13 proteins in the electron transport chain, including 2 subunits of the ATP-synthase. As a result of this the rho0 cells have much lower ATP levels than rho+ cells. In order to mimic the ATP situation in rho0 cells the rho+ cells are incubated with the ATP synthase inhibitor, oligomycin. Similar to the rho0 cells the oligomycin incubated rho+ cells display increased dNTP pools upon UV irradiation.

    Our data shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance.

    OriginalsprogEngelsk
    Publikationsdato2009
    StatusUdgivet - 2009
    Begivenhed13th International Symposium on Purine and Pyrimidine Metabolism in Man - Stockholm, Sverige
    Varighed: 21 jun. 200924 jun. 2009

    Konference

    Konference13th International Symposium on Purine and Pyrimidine Metabolism in Man
    LandSverige
    ByStockholm
    Periode21/06/200924/06/2009

    Citer dette

    Skovgaard, T., Rasmussen, L. J., & Munch-Petersen, B. (2009). Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage. Poster session præsenteret på 13th International Symposium on Purine and Pyrimidine Metabolism in Man, Stockholm, Sverige.
    Skovgaard, Tine ; Rasmussen, Lene Juel ; Munch-Petersen, Birgitte. / Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage. Poster session præsenteret på 13th International Symposium on Purine and Pyrimidine Metabolism in Man, Stockholm, Sverige.
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    title = "Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage",
    abstract = "Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types. In order to further study the interconnection between dNTP pools and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect on the dNTP pools in rho0 cells but not in rho+ cells. In the rho0 cells a 2-3 fold increase in all four deoxynucleotides is observed.Besides from tRNAs and mRNAs the mitochondrial genome is encoding 13 proteins in the electron transport chain, including 2 subunits of the ATP-synthase. As a result of this the rho0 cells have much lower ATP levels than rho+ cells. In order to mimic the ATP situation in rho0 cells the rho+ cells are incubated with the ATP synthase inhibitor, oligomycin. Similar to the rho0 cells the oligomycin incubated rho+ cells display increased dNTP pools upon UV irradiation. Our data shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance.",
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    Skovgaard, T, Rasmussen, LJ & Munch-Petersen, B 2009, 'Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage' 13th International Symposium on Purine and Pyrimidine Metabolism in Man, Stockholm, Sverige, 21/06/2009 - 24/06/2009, .

    Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage. / Skovgaard, Tine; Rasmussen, Lene Juel; Munch-Petersen, Birgitte.

    2009. Poster session præsenteret på 13th International Symposium on Purine and Pyrimidine Metabolism in Man, Stockholm, Sverige.

    Publikation: KonferencebidragPosterForskning

    TY - CONF

    T1 - Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage

    AU - Skovgaard, Tine

    AU - Rasmussen, Lene Juel

    AU - Munch-Petersen, Birgitte

    PY - 2009

    Y1 - 2009

    N2 - Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types. In order to further study the interconnection between dNTP pools and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect on the dNTP pools in rho0 cells but not in rho+ cells. In the rho0 cells a 2-3 fold increase in all four deoxynucleotides is observed.Besides from tRNAs and mRNAs the mitochondrial genome is encoding 13 proteins in the electron transport chain, including 2 subunits of the ATP-synthase. As a result of this the rho0 cells have much lower ATP levels than rho+ cells. In order to mimic the ATP situation in rho0 cells the rho+ cells are incubated with the ATP synthase inhibitor, oligomycin. Similar to the rho0 cells the oligomycin incubated rho+ cells display increased dNTP pools upon UV irradiation. Our data shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance.

    AB - Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types. In order to further study the interconnection between dNTP pools and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect on the dNTP pools in rho0 cells but not in rho+ cells. In the rho0 cells a 2-3 fold increase in all four deoxynucleotides is observed.Besides from tRNAs and mRNAs the mitochondrial genome is encoding 13 proteins in the electron transport chain, including 2 subunits of the ATP-synthase. As a result of this the rho0 cells have much lower ATP levels than rho+ cells. In order to mimic the ATP situation in rho0 cells the rho+ cells are incubated with the ATP synthase inhibitor, oligomycin. Similar to the rho0 cells the oligomycin incubated rho+ cells display increased dNTP pools upon UV irradiation. Our data shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance.

    M3 - Poster

    ER -

    Skovgaard T, Rasmussen LJ, Munch-Petersen B. Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage. 2009. Poster session præsenteret på 13th International Symposium on Purine and Pyrimidine Metabolism in Man, Stockholm, Sverige.