Pesticide avermectin B1a exerts cytotoxicity by blocking the interaction between mini-chromosome maintenance 6 protein (MCM6) and chromatin licensing and DNA replication factor 1 (CDT1).

Autor: Yin H; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Laboratory for Molecular Identification and Biological Evaluation of Chinese Herbal Pieces, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Zheng Y; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Laboratory for Molecular Identification and Biological Evaluation of Chinese Herbal Pieces, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Chen M; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Laboratory for Molecular Identification and Biological Evaluation of Chinese Herbal Pieces, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Ding M; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China; Laboratory for Molecular Identification and Biological Evaluation of Chinese Herbal Pieces, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Zhang L; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Wang R; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Wang C; Level Three Laboratory of Traditional Chinese Medicine Preparation of National Administration of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China., Jia J; Laboratory for Molecular Identification and Biological Evaluation of Chinese Herbal Pieces, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China. Electronic address: imjiajing@163.com., Liu X; Department of Pharmacy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, China. Electronic address: suzhou-0916@163.com.
Jazyk: angličtina
Zdroj: Environmental pollution (Barking, Essex : 1987) [Environ Pollut] 2025 Jan 01; Vol. 364 (Pt 2), pp. 125377. Date of Electronic Publication: 2024 Nov 22.
DOI: 10.1016/j.envpol.2024.125377
Abstrakt: Avermectin B1a, a widely used pesticide, has recently raised safety concerns since it possesses potential cytotoxicity toward mammalian cells. Nevertheless, the exact mechanisms that underlie the cytotoxicity induced by avermectin B1a remain elusive. The loading of the mini-chromosome maintenance 6 protein (MCM6) onto chromatin at replication origins by chromatin licensing and DNA replication factor 1 (CDT1) is an essential step for licensing DNA for replication. Here, we first report that avermectin B1a occupies the CDT1-binding domain (CBD) of MCM6 to block the interaction between MCM6 and CDT1 and thus inhibits the licensing for DNA replication. Avermectin B1a inhibits the proliferation with IC 50 being 15.1 μM and induces cell cycle arrest at the G 0 /G 1 phase in MEF cells. Moreover, abnormal replication licensing induced by avermectin B1a causes replication stress and DNA double strand breaks, which in turn leads to apoptosis in MEF cells. Further molecular docking uncovers that four residues Glu763, Ile760, Arg771, and Glu774 are vital for the formation of hydrogen bonds in avermectin B1a-CBD interaction. Furthermore, the upregulation of MCM6 or/and CDT1 reverses the avermectin B1a-induced decrease in cell viability and normalizes the cell cycle, indicating that the blockage of MCM6-CDT1 interaction is one of the mechanisms underlying avermectin B1a-induced cytotoxicity. This study not only provides new insights into the mechanism of avermectin B1a-induced cytotoxicity but also offers a useful molecular tool for the investigation of MCM6-CDT1 interaction.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Liu Xiaoqian reports financial support was provided by Shandong Province Medical and Health Technology Project. Jia Jing reports financial support was provided by Shandong Provincial Traditional Chinese Medicine Technology Project. Jia Jing reports financial support was provided by Shandong Provincial Postdoctoral Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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