Abstract
Lesions in the DNA arise under ionizing irradiation conditions or various chemical oxidants as a single damage or as part of a multiply damaged site within 1–2 helical turns (clustered lesion). Here, we explored the repair opportunity of the apurinic/apyrimidinic site (AP site) composed of the clustered lesion with 5-formyluracil (5-foU) by the base excision repair (BER) proteins. We found, that if the AP site is shifted relative to the 5-foU of the opposite strand, it could be repaired primarily via the short-patch BER pathway. In this case, the cleavage efficiency of the AP site-containing DNA strand catalyzed by human apurinic/apyrimidinic endonuclease 1 (hAPE1) decreased under AP site excursion to the 3'-side relative to the lesion in the other DNA strand. DNA synthesis catalyzed by DNA polymerase lambda was more accurate in comparison to the one catalyzed by DNA polymerase beta. If the AP site was located exactly opposite 5-foU it was expected to switch the repair to the long-patch BER pathway. In this situation, human processivity factor hPCNA stimulates the process.
Highlights
During the cell cycle, the DNA bases are modified by different endogenous factors in the cellular milieu
The capacity of the endonuclease activity of human apurinic/apyrimidinic endonuclease 1 (hAPE1) to cleave the apyrimidinic site (AP site) located in one DNA strand close to the 5-foU of the other strand was first investigated
DNA synthesis during short-patch base excision repair (BER) pathway catalyzed by DNA polymerase lambda was clearly more accurate than the process carried out by DNA polymerase beta
Summary
The DNA bases are modified by different endogenous factors in the cellular milieu. Unfavorable exogenous physicochemical factors (such as ionizing irradiation, UVA- and UVB-rays, cigarette smoke, products of incomplete combustion fuel in the atmosphere or drug treatment) are important boosters of DNA damage. The action of ionizing irradiation or active/radical forms of oxygen leads to the formation of multiple DNA lesions. Lesions located in the range of one or two turns of the DNA helix are designated multiply damaged sites or clusters. Using computer simulation algorithm it was calculated that the action of high linear energy transfer irradiation could result in cluster formation containing 10–25 individual damages to 100–200 base pairs [1]. Tandem lesions located in one or two DNA strands potentially enhance the risk of the appearance of mutations, since cluster may include a few types of lesions that can be removed from the DNA by different repair systems depending on their nature
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