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oai:repisalud.isciii.es:20.500.12105/78662024-11-29T13:28:07Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2016-02-15 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. Nat Commun. 2016 ;7:10660. 10.1038/ncomms10660 2041-1723 2041-1723 Nature communications 26876348 http://hdl.handle.net/20.500.12105/7866 A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells