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

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

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...

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Main Authors: Ge, Xin Quan, Han, Jinah, Cheng, Ee-Chun, Yamaguchi, Satoru, Shima, Naoko, Thomas, Jean-Leon, Lin, Haifan
Format: Online
Language:English
Published: Elsevier 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618655/
id pubmed-4618655
recordtype oai_dc
spelling pubmed-46186552015-11-24 Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress Ge, Xin Quan Han, Jinah Cheng, Ee-Chun Yamaguchi, Satoru Shima, Naoko Thomas, Jean-Leon Lin, Haifan Report 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. Elsevier 2015-07-16 /pmc/articles/PMC4618655/ /pubmed/26190528 http://dx.doi.org/10.1016/j.stemcr.2015.06.002 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Ge, Xin Quan
Han, Jinah
Cheng, Ee-Chun
Yamaguchi, Satoru
Shima, Naoko
Thomas, Jean-Leon
Lin, Haifan
spellingShingle Ge, Xin Quan
Han, Jinah
Cheng, Ee-Chun
Yamaguchi, Satoru
Shima, Naoko
Thomas, Jean-Leon
Lin, Haifan
Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
author_facet Ge, Xin Quan
Han, Jinah
Cheng, Ee-Chun
Yamaguchi, Satoru
Shima, Naoko
Thomas, Jean-Leon
Lin, Haifan
author_sort Ge, Xin Quan
title Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
title_short Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
title_full Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
title_fullStr Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
title_full_unstemmed Embryonic Stem Cells License a High Level of Dormant Origins to Protect the Genome against Replication Stress
title_sort embryonic stem cells license a high level of dormant origins to protect the genome against replication stress
description 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.
publisher Elsevier
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618655/
_version_ 1613492232959033344

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