Smad5 gene is thought to relay signals of bone morphogenetic protein (BMP) pathway.We have previously shown that the targeted knockout of Smad5 gene resulted in massive apoptosis in mesenchymal cells in vivo and cardiomyocytes derived from ES cells differentiation in vitro.As ES cells can contribute precursors to all adult cell lineages.Consequently, damage to ES cell genomes may cause serious developmental malfunctions.We demonstrate that ES cells lacking Smad5 display an increased sensitivity to UV and Doxorubicin-induced apoptosis and enhanced the responses of ES cells to transforming growth factor-β (TGFβ) stimulation.