Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells
Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells
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DOI：
10.1016/j.stemcr.2020.04.004
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发表时间：
2020-06-09
影响因子：
5.9
通讯作者：
Andrews, Peter W.
中科院分区：
文献类型：
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作者：
Halliwell, Jason A.;Frith, Thomas J. R.;Andrews, Peter W.
人类多能干细胞（PSC）在长期培养中会出现复发性遗传变异。我们现在已经发现，与同基因分化细胞相比，PSC在细胞周期的S期表现出相当多的DNA损伤的证据，显然是由于DNA复制应激，其特征是DNA复制进展较慢，潜在的复制起点激活，复制叉崩溃。在许多癌症中，像PSC一样，表现出缩短的G1期和DNA复制应激，由此产生的DNA损伤可能是PSC中异常和流产有丝分裂发生率较高的基础，导致染色体非异常连接或细胞死亡。然而，我们已经发现，DNA复制应激、DNA损伤和随之而来的异常有丝分裂的程度可以通过在外源核苷存在下培养PSC而显著降低，从而改善存活率、克隆形成和群体增长。
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.