Particulate Hexavalent Chromium Inhibits E2F1 Leading to Reduced RAD51 Nuclear Foci Formation in Human Lung Cells.

Rachel M Speer, Jennifer H Toyoda, Tayler J Croom-Perez, Ke Jian Liu, John Pierce Wise

Toxicological sciences : an official journal of the Society of Toxicology 2021 Apr 27

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Lung cancer is the leading cause of cancer death; however, the mechanisms of lung carcinogens are poorly understood. Metals, including hexavalent chromium [Cr(VI)], induce chromosome instability, an early event in lung cancer. Failure of homologous recombination repair is a key mechanism for chromosome instability. Particulate Cr(VI) causes DNA double-strand breaks and prolonged exposure impairs homologous recombination targeting a key effector protein in this pathway, RAD51. Reduced RAD51 protein is a key endpoint of particulate Cr(VI) exposure. It is currently unknown how Cr(VI) reduces RAD51 protein. E2F1 is the predominant transcription factor for RAD51. This study sought to identify if E2F1 modulates the RAD51 response to particulate Cr(VI). Particulate Cr(VI) reduced RAD51 protein and mRNA levels but had a minimal effect on RAD51 half-life. E2F1 protein and mRNA were also inhibited by particulate Cr(VI) exposure. To connect these two outcomes, we tested if modulating E2F1 affects RAD51 outcomes after particulate Cr(VI) exposure. E2F1 knockdown inhibited RAD51 nuclear foci formation after acute particulate Cr(VI) exposure. These data indicate reduced RAD51 protein levels after prolonged particulate Cr(VI) exposure are predominantly due to inhibited expression. Particulate Cr(VI) also inhibits E2F1 expression. However, although loss of E2F1 does not modulate RAD51 expression after particulate Cr(VI) exposure, RAD51 nuclear foci formation is inhibited. These findings suggest E2F1 is important for RAD51 localization to double-strand breaks, but not expression after particulate Cr(VI) exposure in human lung cells. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Rachel M Speer, Jennifer H Toyoda, Tayler J Croom-Perez, Ke Jian Liu, John Pierce Wise. Particulate Hexavalent Chromium Inhibits E2F1 Leading to Reduced RAD51 Nuclear Foci Formation in Human Lung Cells. Toxicological sciences : an official journal of the Society of Toxicology. 2021 Apr 27;181(1):35-46