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Published on: September 7, 2013
Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice
David A Goukassian1, Elizabeth Helms, Harry van Steeg
1Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA. dgoukass@bu.edu
Abstract:
UV-induced DNA damage gives rise to mutations and skin cancer. We have previously reported that treatment of skin cells in vitro with thymidine dinucleotide (pTT) activates p53 and increases the ability of cells to repair subsequent UV-induced DNA damage by enhancing endogenous DNA repair capacity. Here we show that topical pTT pretreatment enhances the rate of DNA photoproduct removal, decreases UV-induced mutations, and reduces photocarcinogenesis in UV-irradiated hairless WT repair-proficient and Xpc(+/-) heterozygous partially repair-deficient mice, both transgenic for the lacZ/pUR288 mutation-indicator gene. These data support the existence of inducible mammalian DNA damage responses that increase DNA repair capacity after DNA damage and hence reduce the impact of future exposures to environmental carcinogens. The ability of topically applied pTT to induce protective physiologic responses that normally result from DNA damage suggests a previously undescribed means of reducing skin cancer in high-risk individuals.
Insights
Topical thymidine dinucleotide (pTT) pretreatment enhances DNA repair and reduces UV-induced mutations and skin cancer in mice. This suggests a new strategy for preventing skin cancer by boosting natural protective responses.
Area of Science:
- Molecular Biology
- Dermatology
- Cancer Research
Background:
- UV radiation causes DNA damage, leading to mutations and skin cancer.
- Previous research showed thymidine dinucleotide (pTT) activates p53 and DNA repair in vitro.
- Inducible DNA damage responses may enhance repair capacity and reduce carcinogen impact.
Purpose of the Study:
- To investigate the in vivo effects of topical pTT on UV-induced DNA damage and photocarcinogenesis.
- To determine if pTT pretreatment can enhance DNA repair and reduce mutations in mice.
- To explore pTT as a potential preventative measure against skin cancer.
Main Methods:
- Hairless WT and Xpc(+/-) mice transgenic for lacZ/pUR288 were pretreated with topical pTT.
- Mice were exposed to UV irradiation.
- DNA photoproduct removal rates, mutation frequencies, and tumor development were assessed.
Main Results:
- Topical pTT pretreatment significantly enhanced the rate of DNA photoproduct removal.
- pTT treatment decreased UV-induced mutations in the indicator gene.
- Photocarcinogenesis was reduced in pTT-pretreated mice, including those with partial DNA repair deficiency.
Conclusions:
- Topical pTT induces protective physiological responses, enhancing DNA repair capacity.
- These findings support the existence of inducible mammalian DNA damage responses.
- Topical pTT offers a novel approach to reduce skin cancer risk by boosting natural defenses.
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