Molecular mechanisms for ultraviolet radiation-induced mutagenesis and genomic instability
Project leader: Jostein Dahle
The mechanisms of ultraviolet induced mutagenesis and genomic instability are important to understand to be able to prevent skin cancer. This project group has pioneered studies of genomic instability induced by ultraviolet radiation. Although large progress has been made in investigating the mechanisms for skin carcinogenesis, many fundamental questions concerning how ultraviolet radiation interacts with skin and cells remain unanswered. This lack of knowledge has been a key obstacle in the development of effective prevention of skin cancer, particularly malignant melanoma. Results from this project group may contribute to improving knowledge on which advice to the general public about ultraviolet radiation exposure is based. The principal objective of the project is to determine the molecular mechanisms of ultraviolet radiation induced genomic instability to enable identification of targets for sun cream and drug development and biomarkers for disease monitoring.
The mechanisms of ultraviolet induced mutagenesis and genomic instability are important to understand to be able to prevent skin cancer. This project group has pioneered studies of genomic instability induced by ultraviolet radiation. Although large progress has been made in investigating the mechanisms for skin carcinogenesis, many fundamental questions concerning how ultraviolet radiation interacts with skin and cells remain unanswered. This lack of knowledge has been a key obstacle in the development of effective prevention of skin cancer, particularly malignant melanoma. Results from this project group may contribute to improving knowledge on which advice to the general public about ultraviolet radiation exposure is based. The principal objective of the project is to determine the molecular mechanisms of ultraviolet radiation induced genomic instability to enable identification of targets for sun cream and drug development and biomarkers for disease monitoring.
Important results from the project
Mutation frequency measured in clones more than 23 cell generations (14 days) after irradiation with D20 doses of UVA-radiation, UVB radiation or X-radiation. Cells were cloned immediately after irradiation. The numbers in the black area are the percentage of clones with mutation frequency below the detection limit for the assay. Unstable clones are defined as clones with mutation frequencies above 10×10-6.
Ultraviolet radiation-induced mutations have been assumed to be the result of DNA damage inflicted directly by the radiation. This DNA damage is converted to a mutation either during DNA replication or as the result of errors during DNA repair, and mutations should therefore occur shortly after irradiation. However, recent evidence from our lab suggests that increased mutation frequencies can occur 23 cell generations after ultraviolet irradiation. By cloning cells immediately after irradiation and culturing them for 23 cell generations before measuring mutation frequency, UVA radiation was found to be as effective as UVB radiation in inducing delayed mutations. Around 10 % of these cell clones exhibited increased delayed mutation frequencies. Thus, both UVA- and UVB radiation is able to disrupt cellular homeostasis such that the memory of past insult is perpetuated over multiple cellular generations. This result is quite remarkable because UVB radiation is around ten times more effective than UVA radiation in inducing early mutations.
Further studies
Ultraviolet radiation is the main radiation type used in this project, while the major international research groups in the radiation-induced genomic instability field mainly use ionizing radiation.
The role of oxidative stress in UV-induced genomic instability and mutagenesis
There are strong indications that oxidative stress has a major role in ionizing radiation induced genomic instability. Recently, we have obtained results indicating that oxidative stress is important also for UV-induced genomic instability.
The role of DNA repair in UV-induced genomic instability and mutagenesis
Repair of DNA is essential for maintaining genomic instability and protecting against cancer. Base excision repair (BER) and nucleotide excision repair (NER) are involved in repairing UV-induced DNA damage. However, the role of DNA repair in radiation induced genomic instability is unknown.
The role of the bystander effect in UV-induced genomic instability
The bystander effect is the effect of irradiated cells or medium from irradiated cells on unirradiated neighbouring cells. By mathematical modelling we have earlier shown that the bystander effect is involved in cell death using a photosensitizer and blue light or UVA radiation. The role of the bystander effect in radiation-induced genomic instability is principal objective of this sub project.
The role of oxidative stress in UV-induced genomic instability and mutagenesis
There are strong indications that oxidative stress has a major role in ionizing radiation induced genomic instability. Recently, we have obtained results indicating that oxidative stress is important also for UV-induced genomic instability.
The role of DNA repair in UV-induced genomic instability and mutagenesis
Repair of DNA is essential for maintaining genomic instability and protecting against cancer. Base excision repair (BER) and nucleotide excision repair (NER) are involved in repairing UV-induced DNA damage. However, the role of DNA repair in radiation induced genomic instability is unknown.
The role of the bystander effect in UV-induced genomic instability
The bystander effect is the effect of irradiated cells or medium from irradiated cells on unirradiated neighbouring cells. By mathematical modelling we have earlier shown that the bystander effect is involved in cell death using a photosensitizer and blue light or UVA radiation. The role of the bystander effect in radiation-induced genomic instability is principal objective of this sub project.
Research projects for master of science students
We have several research projects for Master of Science students. {link}
Environment
The project is part of the group for Molecular Radiation Biology at the Department of Biophysics.
Trond Stokke is the leader of the group. {link}.
We collaborate with Gunnar Brunborg (The Norwegian Institute of Public Health) {link} on measurement of DNA repair and with Rune Blomhoff (Institute of Nutrition, University of Oslo) {link} on measurement of antioxidant potential.
Trond Stokke is the leader of the group. {link}.
We collaborate with Gunnar Brunborg (The Norwegian Institute of Public Health) {link} on measurement of DNA repair and with Rune Blomhoff (Institute of Nutrition, University of Oslo) {link} on measurement of antioxidant potential.
Methods
Some of the methods used by the group are described briefly here. {link}
Project publications
Dahle, J., Kvam, E. Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB- and X-radiation. (2003) Cancer Research 63 pp. 1464-1469.
Dahle, J., Kaalhus, O., Moan, J., Steen, H., B., Cooperative effects on cells treated with Photofrin and light. (1997) Proc. Natl. Acad. Sci. USA. 94 p. 1773-1778.
Dahle, J., Kaalhus, O., Moan, J., Steen, H., B., Cooperative effects on cells treated with Photofrin and light. (1997) Proc. Natl. Acad. Sci. USA. 94 p. 1773-1778.
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