title: Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress.
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.
authors.affiliation: Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xin Quan
authors.initials: XQ
authors.lastname: Ge
authors.affiliation: Yale Cardiovascular Research Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jinah
authors.initials: J
authors.lastname: Han
authors.affiliation: Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ee-Chun
authors.initials: EC
authors.lastname: Cheng
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shima
authors.affiliation: Yale Cardiovascular Research Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jean-Leon
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Haifan
authors.initials: H
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D042822:Genomic Instability; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D018741:Replication Origin; D013312:Stress, Physiological