Modification of DNA repair enzymes by oxidative stress and cancer progression

Oxidative stress and lipid peroxidation (LPO) are involved in the pathogenesis of several human diseases, including cancer. LPO products react with proteins and with DNA bases to form exocyclic DNA adducts of different size and high mutagenic potency. Ethenoadducts are removed mainly by Base Excision Repair (BER) pathway, while bulky adducts of LPO products by Nucleotide Excision Repair (NER). BER is deregulated in colon and lung cancers. One of the major reactive aldehyde generated by LPO, trans-4-hydroxy-2-nonenal (HNE) inhibits NER activity, both global genome repair (GGR) and transcription coupled repair (TCR). BER system is affected as well. The activity of purified ANPG and TDG glycosylases, but not of APE1 endonuclease and OGG1 glycosylase are inhibited only by high concentrations of HNE. However, when cells are pretreated with physiological HNE concentrations the rate of excision of 1,N6-ethenoadenine and 3,N4-ethenocytosine, but not of 8-oxoguanine are decreased in comparison to untreated cells. Simultaneously HNE increases the rate of AP site incision and blocks the religation step after filling the gap by DNA polymerases. Such imbalance in different stages of BER results in augmentation of the level of DNA strand breaks, and sensitizes cells to oxidative and alkylating agents, H2O2 and MMS. Thus, LPO products may, both, form DNA adducts, and deregulate activities of BER and NER enzymes. This may have an impact on cell survival and genome stability, and may be an additional mechanism of pro-carcinogenic effect of inflammation. Carcinogenic process also affects DNA repair enzymes. Several signaling proteins regulate transcription and/or activity of different repair proteins. APC gene product inhibits APE1 and FEN1 endonucleases as well as DNA polymerase b in BER pathway. TP53 protein regulates expression of APE1, EGF receptor may activate nonhomologous end joining. Thus, during carcinogenic process repair of oxidative DNA damage is deregulated by the products of oxidative stress and mutated signaling proteins. L1.2