title: High mitochondrial priming sensitizes hESCs to DNA-damage-induced apoptosis.
abstract: Human embryonic stem cells (hESCs) are highly sensitive to DNA damage and have low survival ability relative to differentiated cells. We investigated the source of this difference by comparing damage response pathways in hESCs and differentiated cells. We found that hESCs undergo more rapid p53-dependent apoptosis after DNA damage than differentiated cells do. However, p53 localization and function are similar between hESCs and differentiated cells, suggesting that p53 alone cannot explain the difference in sensitivity. Instead, we show that mitochondrial readiness for apoptosis, known as mitochondrial priming, differs between hESCs and differentiated cells. Specifically, the balance between proapoptotic and antiapoptotic proteins is shifted closer to the apoptotic threshold in hESCs than in differentiated cells. Altering this balance in differentiated cells increases their sensitivity and results in cell death, suggesting that manipulation of mitochondrial priming could potentially alter the sensitivity of other stem cells, including cancer stem cells.
authors: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors: Julia C
authors: JC
authors: Liu
authors: Xiao
authors: X
authors: Guan
authors: Jeremy A
authors: JA
authors: Ryan
authors: Ana G
authors: AG
authors: Rivera
authors: Caroline
authors: C
authors: Mock
authors: Vishesh
authors: V
authors: Agrawal
authors: Vishesh
authors: V
authors: Agarwal
authors: Anthony
authors: A
authors: Letai
authors: Paul H
authors: PH
authors: Lerou
authors: Galit
authors: G
authors: Lahav
mesh_terms: D017209:Apoptosis; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53
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