Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells


Human pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death. However, we have found that the extent of DNA replication stress, DNA damage, and consequent aberrant mitoses can be substantially reduced by culturing PSCs in the presence of exogenous nucleosides, resulting in improved survival, clonogenicity, and population growth. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Authors Halliwell JA, Frith TJR, Laing O, Price CJ, Bower OJ, Stavish D, Gokhale PJ, Hewitt Z, El-Khamisy SF, Barbaric I, Andrews PW
Journal Stem cell reports
Publication Date 2020 Jun 9;14(6):1009-1017
PubMed 32413278
PubMed Central PMC7355123
DOI 10.1016/j.stemcr.2020.04.004

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