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RESEARCH PRODUCT

ATR expands embryonic stem cell fate potential in response to replication stress

Sara Samadi ShamsEndre SebestyénSina AtashpazValeria CancilaNegar ArghavanifardEliene AlbersJavier Martin GonzalezOscar Fernandez-capetilloGiovanni FagaAngela BachiVincenzo CostanzoElisa AllieviFrancesco FerrariAndrea GnocchiPaolo SoffientiniSimone MinardiClaudio TripodoAndrés J. López-contreras

subject

0301 basic medicineEndogenyAtaxia Telangiectasia Mutated ProteinsMice0302 clinical medicineTandem Mass SpectrometryTranscription (biology)GENE ATRcell biologyCloning MolecularBiology (General)Cells Cultured0303 health sciencesGeneral NeuroscienceQRTotipotentCell DifferentiationEmbryoGeneral MedicineCell biologyMedicinebiological phenomena cell phenomena and immunityResearch ArticleQH301-705.5replication stressDNA damageScienceSettore MED/08 - Anatomia PatologicaBiologyGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciencesAnimalsRNA MessengerGeneEmbryonic Stem CellsmouseCell Proliferation030304 developmental biologyMessenger RNAGeneral Immunology and MicrobiologyChimeraSequence Analysis RNAEmbryogenesisTELOMERE ELONGATIONEPIGENETIC RESTRICTIONembryonic stem cellEmbryonic stem cellATR030104 developmental biologyGene Expression RegulationDNA-DAMAGECheckpoint Kinase 1GENOMIC STABILITY030217 neurology & neurosurgeryChromatography LiquidDNA Damage

description

Fondazione Italiana per la Ricerca sul Cancro FIRC 18112 Sina Atashpaz.Fondazione Umberto Veronesi Sina Atashpaz Associazione Italiana per la Ricerca sul Cancro AIRC 5xmille METAMECH program Vincenzo Costanzo Giovanni Armenise-Harvard Foundation Vincenzo Costanzo European Research Council Consolidator grant 614541 Vincenzo Costanzo Associazione Italiana per la Ricerca sul Cancro Fellowship 23961 Negar ArghavanifarDanish Cancer Society KBVU-2014 Andres Joaquin Lopez-Contreras Danish Council for Independent Research Sapere Aude, DFF Starting Grant 2014 Andres Joaquin Lopez-Contreras European Research Council ERC-2015-STG-679068 Andres Joaquin Lopez-Contreras Danish National Research Foundation DNRF115 Andres Joaquin Lopez-Contreras The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS. Sí

yearjournalcountryeditionlanguage
2020-03-01eLife
https://doi.org/10.7554/elife.54756