Effect of Human XRCC1 Protein Oxidation on the Functional Activity of Its Complexes with the Key Enzymes of DNA Base Excision Repair

I. A. Vasil’eva, N. A. Moor, O. I. Lavrik

Результат исследования: Научные публикации в периодических изданияхстатья

Аннотация

Base excision repair (BER) ensures correction of most abundant DNA lesions in mammals. The efficiency of this multistep DNA repair process that can occur via different pathways depends on the coordinated action of enzymes catalyzing its individual steps. The scaffold XRCC1 (X-ray repair cross-complementing protein 1) protein plays an important coordinating role in the repair of damaged bases and apurinic/apyrimidinic (AP) sites via short-patch (SP) BER pathway, as well as in the repair of single-strand DNA breaks. In this study, we demonstrated for the first time in vitro formation of the ternary XRCC1 complex with the key enzymes of SP BER — DNA polymerase β (Polβ) and DNA ligase IIIa (LiglIIa) — using the fluorescence-based technique. It was found that Polβ directly interacts with LiglIIa, but their complex is less stable than the XRCC1—Polβ and XRCC1—LigIIIa complexes. The effect of XRCC1 oxidation and composition of the multiprotein complex on the efficiency of DNA synthesis and DNA ligation during DNA repair has been explored. We found that formation of the disulfide bond between Cys12 and Cys20 residues as a result of XRCC1 oxidation (previously shown to modulate the protein affinity for Polβ), affects the yield of the final product of SP BER and of non-ligated DNA intermediates (substrates of long-patch BER). The effect of XRCC1 oxidation on the final product yield depended on the presence of AP endonuclease 1. Together with the data from our previous work, the results of this study suggest an important role of XRCC1 oxidation in the fine regulation of formation of BER complexes and their functional activity.

Язык оригиналаанглийский
Страницы (с-по)288-299
Число страниц12
ЖурналBiochemistry (Moscow)
Том85
Номер выпуска3
DOI
СостояниеОпубликовано - 22 мар 2020

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