High glutathione and glutathione peroxidase-2 levels mediate cell-type-specific DNA damage protection in human induced pluripotent stem cells.
Pluripotent stem cells must strictly maintain genomic integrity to prevent transmission of mutations. In human induced pluripotent stem cells (iPSCs), we found that genome surveillance is achieved via two ways, namely, a hypersensitivity to apoptosis and a very low accumulation of DNA lesions. The low apoptosis threshold was mediated by constitutive p53 expression and a marked upregulation of proapoptotic p53 target genes of the BCL-2 family, ensuring the efficient iPSC removal upon genotoxic insults. Intriguingly, despite the elevated apoptosis sensitivity, both mitochondrial and nuclear DNA lesions induced by genotoxins were less frequent in iPSCs compared to fibroblasts. Gene profiling identified that mRNA expression of several antioxidant proteins was considerably upregulated in iPSCs. Knockdown of glutathione peroxidase-2 and depletion of glutathione impaired protection against DNA lesions. Thus, iPSCs ensure genomic integrity through enhanced apoptosis induction and increased antioxidant defense, contributing to protection against DNA damage.
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Benjamin
B
Dannenmann
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Simon
S
Lehle
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Dominic G
DG
Hildebrand
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Ayline
A
Kübler
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Paula
P
Grondona
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Vera
V
Schmid
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Katharina
K
Holzer
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Mirjam
M
Fröschl
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Frank
F
Essmann
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Oliver
O
Rothfuss
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: kso@uni-tuebingen.de.
Klaus
K
Schulze-Osthoff
D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; D005978:Glutathione