Genotoxins exaggerate the stressed state of aneuploid embryonic stem cells via activation of autophagy

The cellular consequences of aneuploidy are largely dependent on the cell types examined. Aneuploid yeasts and mouse embryonic fibroblasts exhibit cell proliferation defects and can be selectively inhibited by compounds that cause proteotoxic or energy stress. By contrast, most aneuploid pluripotent stem cells proliferate rapidly and reach higher saturation densities. The responses of aneuploid pluripotent stem cells to the stress-inducing compounds remain uncharacterized. Here, we tested the response of aneuploid embryonic stem cells to several compounds that caused proteotoxic, energy and genotoxic stress using previously established mouse embryonic stem cell lines trisomic for chromosome 6, 8, 11, or 15. Not all trisomic embryonic stem cells were selectively inhibited by compounds that cause proteotoxic or energy stress. However, most of these cells exhibited increased sensitivity to genotoxins. They displayed elevated DNA damage response as characterized by increased γH2A.X foci under genotoxic stress. Further investigations indicated that elevated autophagy levels might contribute to the increased cytotoxic effects of genotoxins on trisomic embryonic stem cells. Our study laid the foundation for eliminating aneuploidy that might be an effective approach for controlling cancer progression.