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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Currently there are more than 200 completed or running clinical trials for the PARP inhibitors (PARPis). Four of them (olaparib, rucaparib, niraparib and talazoparib) have been approved by FDA for treating ovarian and breast cancers. It is assumed that their anti-cancer effect is associated with inhibition of the PARP catalytic activity. Recent studies have shown that PARPis also exert their cytotoxicity by trapping PARP-DNA complexes. Potency to trap PARP–DNA complexes varies widely among PARPis and often does not correlate with their ability to inhibit PARP catalytic activity. This differential trapping potency can potentially originate from an allosteric change in protein conformation leading to an increase in binding activity. We have studied the mechanism of PARP1 trapping using fluorescently labeled mononucleosomes as “minimal” experimental system that recapitulates interaction of PARP1 with DNA in chromatin. PARP trapping by three PARPis and gel-shift analysis. Our studies revealed that PARP1 forms three types of complexes with the mononucleosome; one of them induces partial nucleosome unfolding that we have described previously. In the presence of NAD+, only the unfolded PARP-nucleosome complex was trapped by PARPis, suggesting that the PARPis-induced PARP trapping strongly depends on the structure of PARP-nucleosome complex. The new proposed approach to identification of the trapped complexes can be useful for the development of efficient PARPis with increased trapping and cytotoxic activity. This study was supported by RFBR grant 17-54-33045