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

Valeria Cancila, Claudio Tripodo, Endre Sebestyén, Sina Atashpaz, Francesco Ferrari, Sara Samadi Shams, Negar Arghavanifard, Óscar Fernández-Capetillo, Eliene Albers, Javier Martin Gonzalez, Elisa Allievi, Andrea Gnocchi, Francesco Ferrari, Paolo Soffientini, Giovanni Faga, Vincenzo Costanzo, Angela Bachi, Simone Minardi, Andrés Joaquin López-Contreras

Risultato della ricerca: Articlepeer review

22 Citazioni (Scopus)


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.
Lingua originaleEnglish
Numero di pagine0
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.1300.1300???
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