期刊
CELLS
卷 11, 期 21, 页码 -出版社
MDPI
DOI: 10.3390/cells11213343
关键词
poly(ADP-ribose-)polymerase-1; PARP1 inhibitors; talazoparib; olaparib; veliparib; nucleosome; chromatin
类别
资金
- Russian Science Foundation [21-64-0001]
The cytotoxicity of poly(ADP-ribose-)polymerase-1 (PARP1) inhibitors (PARPi) in antitumor therapy is correlated with their trapping efficiency in cell chromatin. The interactions of PARP1-nucleosome complexes with PARPi were studied, and it was found that the efficiency of PARP1 trapping on nucleosomes is affected by the chromatin structure.
Inhibitors (PARPi) of poly(ADP-ribose-)polymerase-1 (PARP1) are used in antitumor therapy; their cytotoxicity correlates with the efficiency of PARP1 trapping in cell chromatin. Previous studies have demonstrated the PARPi-induced trapping of PARP1 on DNA, although details of the mechanism remain controversial. Here, the interactions of PARP1-nucleosome complexes with PARPi, olaparib (Ola), talazoparib (Tala), and veliparib (Veli) were studied. PARPi trap PARP1 on nucleosomes without affecting the structure of PARP1-nucleosome complexes. The efficiency of PARP1 trapping on nucleosomes increases in the order of Tala>Ola>>Veli, recapitulating the relative trapping efficiencies of PARPi in cells, but different from the relative potency of PARPi to inhibit the catalytic activity of PARP1. The efficiency of PARP1 trapping on nucleosomes correlates with the level of inhibition of auto-PARylation, which otherwise promotes the dissociation of PARP1-nucleosome complexes. The trapping efficiencies of Tala and Ola (but not Veli) are additionally modulated by the enhanced PARP1 binding to nucleosomes. The dissociation of PARP1-nucleosome complexes occurs without a loss of histones and leads to the restoration of the intact structure of nucleosomal DNA. The data suggest that the chromatin structure can considerably affect the efficiency of the PARPi action.
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