Abstract
Human embryonic stem cells (hESCs) hold great promise for the treatment of many incurable diseases. Sirtuin1 (SIRT1), a class III histone deacetylase, is abundantly expressed in hESCs and is known to regulate early differentiation and telomere elongation. Here, we show that downregulation of SIRT1 promotes cell death in hESCs, but not in differentiated cells, and the SIRT1-inhibition-mediated cell death is preceded by increased DNA damage. This increased DNA damage is at least partially due to decreased levels of DNA repair enzymes such as MSH2, MSH6, and APEX1. Furthermore, SIRT1 inhibition causes p53 activation, which eventually leads to DNA damage-induced apoptosis of hESCs. This study provides valuable insights into the mechanism of SIRT1-mediated hESC survival and should contribute to the development of safe and effective cell therapies.