Oxidative Stress-Induced Protein Damage Inhibits DNA Repair and Determines Mutation Risk and Therapeutic Efficacy.
The relationship between sun exposure and nonmelanoma skin cancer risk is well established. Solar UV (wavelength 280-400 nm) is firmly implicated in skin cancer development. Nucleotide excision repair (NER) protects against cancer by removing potentially mutagenic DNA lesions induced by UVB (280-320 nm). How the 20-fold more abundant UVA (320-400 nm) component of solar UV radiation increases skin cancer risk is not understood. Here it is demonstrated that the contribution of UVA to the effect of UV radiation on cultured human cells is largely independent of its ability to damage DNA. Instead, the effects of UVA reflect the induction of oxidative stress that causes extensive protein oxidation. Because NER proteins are among those damaged, UVA irradiation inhibits NER and increases the susceptibility of the cells to mutation by UVB. NER inhibition is a common consequence of oxidative stress. Exposure to chemical oxidants, treatment with drugs that deplete cellular antioxidants, and interventions that interfere with glucose metabolism to disrupt the supply of cellular reducing power all inhibit NER. Tumor cells are often in a condition of oxidative stress and one effect of the NER inhibition that results from stress-induced protein oxidation is an increased sensitivity to the anticancer drug cisplatin.



As NER is both a defense against cancer and a significant determinant of cell survival after treatment with anticancer drugs, its attenuation by protein damage under conditions of oxidative stress has implications for both cancer risk and for the effectiveness of anticancer therapy. Mol Cancer Res; 14(7); 612-22. ©2016 AACR.
The Francis Crick Institute, Clare Hall Laboratory, South Mimms, Hertfordshire, United Kingdom.
Elizabeth
E
McAdam
The Francis Crick Institute, Clare Hall Laboratory, South Mimms, Hertfordshire, United Kingdom.
Reto
R
Brem
The Francis Crick Institute, Clare Hall Laboratory, South Mimms, Hertfordshire, United Kingdom. peter.karran@crick.ac.uk.
Peter
P
Karran
D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D016296:Mutagenesis / Q000528:radiation effects; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics* / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D014466:Ultraviolet Rays
D017382:Reactive Oxygen Species