Inhibitors of Nucleotide Excision Repair Decrease UVB-Induced Mutagenesis-An In Vitro Study

Area of Science:

• Molecular Biology
• Dermatology
• Pharmacology

Background:

• Chronic ultraviolet B (UVB) exposure causes DNA damage in epidermal cells, leading to skin cancer, particularly in Caucasians.
• Cyclobutane-pyrimidine dimers (CPDs) are key UVB-induced photolesions repaired by nucleotide excision repair (NER).
• Some medications can inhibit NER in vitro, but their impact on skin cancer risk remains unclear.

Purpose of the Study:

• To investigate the effect of four NER-inhibitory molecules (veliparib, resveratrol, spironolactone, arsenic trioxide) on UVB-induced DNA damage and mutations in skin cells.
• To explore the cellular responses and molecular changes associated with NER inhibition following UVB exposure.

Main Methods:

• UVB irradiation of CHO epithelial and HaCaT keratinocyte cell lines.
• Treatment with veliparib, resveratrol, spironolactone, or arsenic trioxide.
• Assessment of CPD levels, gene mutation frequency, cell viability, cell cycle, apoptosis, autophagy, and protein expression (mTOR, mitochondrial fission).

Main Results:

• All four tested molecules increased CPD levels post-UVB irradiation.
• Veliparib, spironolactone, and arsenic trioxide reduced UVB-induced mutations, while resveratrol had no significant effect.
• Spironolactone and arsenic trioxide enhanced UVB-induced apoptosis; veliparib caused cell cycle arrest and autophagy; spironolactone affected mTOR; arsenic trioxide influenced mitochondrial fission.

Conclusions:

• Chemically inhibited NER does not necessarily increase mutagenic effects and can paradoxically mitigate UVB-induced mutations.
• NER inhibitors induce compensatory molecular and metabolic changes in cells, potentially explaining the reduced mutagenic potential.
• Cellular metabolic responses are critical factors in evaluating the skin cancer risk modification by pharmacological compounds.