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Stem Cell Reports. 2015 Aug 11;5(2):185-94. doi: 10.1016/j.stemcr.2015.06.002. Epub 2015 Jul 16.

Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress.

Author information

1
Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Yale Cardiovascular Research Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
4
Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA; SIAIS and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: haifan.lin@yale.edu.

Abstract

Maintaining genomic integrity during DNA replication is essential for stem cells. DNA replication origins are licensed by the MCM2-7 complexes, with most of them remaining dormant. Dormant origins (DOs) rescue replication fork stalling in S phase and ensure genome integrity. However, it is not known whether DOs exist and play important roles in any stem cell type. Here, we show that embryonic stem cells (ESCs) contain more DOs than tissue stem/progenitor cells such as neural stem/progenitor cells (NSPCs). Partial depletion of DOs does not affect ESC self-renewal but impairs their differentiation, including toward the neural lineage. However, reduction of DOs in NSPCs impairs their self-renewal due to accumulation of DNA damage and apoptosis. Furthermore, mice with reduced DOs show abnormal neurogenesis and semi-embryonic lethality. Our results reveal that ESCs are equipped with more DOs to better protect against replicative stress than tissue-specific stem/progenitor cells.

PMID:
26190528
PMCID:
PMC4618655
DOI:
10.1016/j.stemcr.2015.06.002
[Indexed for MEDLINE]
Free PMC Article
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