期刊
CELL REPORTS
卷 3, 期 3, 页码 651-660出版社
CELL PRESS
DOI: 10.1016/j.celrep.2013.02.005
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资金
- Louis V. Gerstner Jr. Young Investigators Award
- Memorial Sloan-Kettering Cancer Center Society Special Projects Committee
- New York State Stem Cell Science fellowship from the Center for Stem Cell Biology of the Sloan-Kettering Institute
- American-Italian Cancer Foundation Postdoctoral Research Fellowship
Induced pluripotent stem cells (iPSCs) hold great promise for personalized regenerative medicine. However, recent studies show that iPSC lines carry genetic abnormalities, suggesting that reprogramming may be mutagenic. Here, we show that the ectopic expression of reprogramming factors increases the level of phosphorylated histone H2AX, one of the earliest cellular responses to DNA double-strand breaks (DSBs). Additional mechanistic studies uncover a direct role of the homologous recombination (HR) pathway, a pathway essential for error-free repair of DNA DSBs, in reprogramming. This role is independent of the use of integrative or nonintegrative methods in introducing reprogramming factors, despite the latter being considered a safer approach that circumvents genetic modifications. Finally, deletion of the tumor suppressor p53 rescues the reprogramming phenotype in HR-deficient cells primarily through the restoration of reprogramming-dependent defects in cell proliferation and apoptosis. These mechanistic insights have important implications for the design of safer approaches to creating iPSCs.
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