Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency

Ryoko Araki (), Yuko Hoki, Tomo Suga, Chizuka Obara, Misato Sunayama, Kaori Imadome, Mayumi Fujita, Satoshi Kamimura, Miki Nakamura, Sayaka Wakayama, Andras Nagy, Teruhiko Wakayama and Masumi Abe ()
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Ryoko Araki: National Institutes for Quantum and Radiological Science and Technology
Yuko Hoki: National Institutes for Quantum and Radiological Science and Technology
Tomo Suga: National Institutes for Quantum and Radiological Science and Technology
Chizuka Obara: National Institutes for Quantum and Radiological Science and Technology
Misato Sunayama: National Institutes for Quantum and Radiological Science and Technology
Kaori Imadome: National Institutes for Quantum and Radiological Science and Technology
Mayumi Fujita: National Institutes for Quantum and Radiological Science and Technology
Satoshi Kamimura: National Institutes for Quantum and Radiological Science and Technology
Miki Nakamura: National Institutes for Quantum and Radiological Science and Technology
Sayaka Wakayama: University of Yamanashi
Andras Nagy: Mount Sinai Hospital
Teruhiko Wakayama: University of Yamanashi
Masumi Abe: National Institutes for Quantum and Radiological Science and Technology

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract A number of point mutations have been identified in reprogrammed pluripotent stem cells such as iPSCs and ntESCs. The molecular basis for these mutations has remained elusive however, which is a considerable impediment to their potential medical application. Here we report a specific stage at which iPSC generation is not reduced in response to ionizing radiation, i.e. radio-resistance. Quite intriguingly, a G1/S cell cycle checkpoint deficiency occurs in a transient fashion at the initial stage of the genome reprogramming process. These cancer-like phenomena, i.e. a cell cycle checkpoint deficiency resulting in the accumulation of point mutations, suggest a common developmental pathway between iPSC generation and tumorigenesis. This notion is supported by the identification of specific cancer mutational signatures in these cells. We describe efficient generation of human integration-free iPSCs using erythroblast cells, which have only a small number of point mutations and INDELs, none of which are in coding regions.

Date: 2020
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DOI: 10.1038/s41467-019-13830-x

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