2026-06-14T03:33:46Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/78662024-11-29T13:28:07Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Ahuja, Akshay K
author
Jodkowska, Karolina
author
Teloni, Federico
author
Bizard, Anna H
author
Zellweger, Ralph
author
Herrador, Raquel
author
Ortega Jimenez, Sagrario
author
Hickson, Ian D
author
Altmeyer, Matthias
author
Mendez, Juan
author
Lopes, Massimo
funder
Danish National Research Foundation
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
2019-07-08T09:13:24Z
2019-07-08T09:13:24Z
2016-02-15
Nat Commun. 2016 ;7:10660.
10.1038/ncomms10660
2041-1723
2041-1723
Nature communications
26876348
http://hdl.handle.net/20.500.12105/7866
Embryonic stem cells (ESCs) represent a transient biological state, where pluripotency is coupled with fast proliferation. ESCs display a constitutively active DNA damage response (DDR), but its molecular determinants have remained elusive. Here we show in cultured ESCs and mouse embryos that H2AX phosphorylation is dependent on Ataxia telangiectasia and Rad3 related (ATR) and is associated with chromatin loading of the ssDNA-binding proteins RPA and RAD51. Single-molecule analysis of replication intermediates reveals massive ssDNA gap accumulation, reduced fork speed and frequent fork reversal. All these marks of replication stress do not impair the mitotic process and are rapidly lost at differentiation onset. Delaying the G1/S transition in ESCs allows formation of 53BP1 nuclear bodies and suppresses ssDNA accumulation, fork slowing and reversal in the following S-phase. Genetic inactivation of fork slowing and reversal leads to chromosomal breakage in unperturbed ESCs. We propose that rapid cell cycle progression makes ESCs dependent on effective replication-coupled mechanisms to protect genome integrity.
eng
A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells
journal article
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AshortG1phaseimposesconstitutive_2016.pdf.txt
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