AI Article Synopsis

  • Avermectin B1a, a commonly used pesticide, raises safety concerns due to its potential to be cytotoxic to mammalian cells, yet its exact mechanisms remain unclear.
  • The study reveals that avermectin B1a disrupts the interaction between mini-chromosome maintenance 6 protein (MCM6) and the DNA replication factor CDT1, preventing proper DNA replication licensing and leading to cell cycle arrest and apoptosis.
  • Molecular analysis identifies key residues in the MCM6-binding domain that interact with avermectin B1a, offering insights into its cytotoxic effects and providing a framework for future studies on MCM6-CDT1 interactions.

Article Abstract

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 being 15.1 μM and induces cell cycle arrest at the G/G 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.

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http://dx.doi.org/10.1016/j.envpol.2024.125377DOI Listing

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