Abstract for presentation at 11th International Congress of Human Genetics

UVA and Ionising radiation induce persistent genomic instability and homologous recombination repair in human skin cells

  • Dr Ursula Jewell, Christchurch School of Medicine, CGRG, Pathology Department, University of Otago, Christchurch, New Zealand, Germany
  • Dr Ross Phillipson, Unit of Biomedical Sciences, Lancaster University, Lancaster, LA1 4YQ, UK, United Kingdom
  • Dr Fiona Benson, Unit of Biomedical Sciences, Lancaster University, Lancaster, LA1 4YQ, UK, United Kingdom
  • Dr Trevor McMillan, Unit of Biomedical Sciences, Lancaster University, Lancaster, LA1 4YQ, UK, United Kingdom

    • Environmental exposure to UVA radiation has been associated experimentally and epidemiologically with malignant melanoma. UVA radiation is absorbed by endogenous chromophores which generate reactive oxygen species (ROS), and leads to indirect DNA, protein, and membrane damage. It also has the ability to penetrate deeper into the skin than UVB, to proliferating basal layers, and causes transient and permanent genetic damage. The resulting phenotype of increased mutation frequency, chromosomal aberrations, and delayed cell death is indicative of persistent genomic instability (PGI), a key element in carcinogenesis. It has been shown that PGI is induced by DNA-damaging agents that produce ROS, e.g. UVA and ionising radiation (IR), but not by agents that damage DNA without ROS. The PGI phenotype bears a strong correlation to the phenotype observed in cells with dysregulated recombination, suggesting a link between the two that could provide a potential amplification mechanism for mutagenic events.
    In this study we applied Real-Time PCR gene expression analysis to identify whether induction of PGI by exposure of human skin keratinocytes to environmentally and clinically relevant doses of UVA and IR, respectively, causes a modulation of the homologous recombination repair (HRR) capacity of cells.
    Gene expression profiles of a number of genes critical for HRR showed a significant increase in mRNA after irradiation. Expression of RAD51 mRNA levels increased 5-fold and 3-fold between 1 and 3 days after cells were exposed to UVA and IR respectively. Within the same time-frame RAD52 mRNA levels increased up to 10-fold and 4-fold, respectively, and also RAD51D mRNA levels. No significant alteration in RAD51C was detected.
    These results show that exposure to UVA and IR increases expression of HRR-genes in human skin cells and support the suggestion that induction of PGI causes a transient shift in the HRR capacity of cells to a “hyper-recombinogenic” state.

    Conference Organiser - ICMS Pty Ltd