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

Atashpaz, S.; Samadi Shams, S.; Gonzalez, J. M.; Sebestyen, E.; Arghavanifard, N.; Gnocchi, A.; Albers, E.; Minardi, S.; Faga, G.; Soffientini, P.; Allievi, E.; Cancila, V.; Bachi, A.; Fernandez-Capetillo, O.; Tripodo, C.; Ferrari, F.; Lopez-Contreras, A. J.; Costanzo, V.

doi:10.1101/2020.01.01.888354

bioRxiv · 10.1101/2020.01.01.888354

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

Atashpaz, S.·Samadi Shams, S.·Gonzalez, J. M.·Sebestyen, E.·Arghavanifard, N.·Gnocchi, A.·Albers, E.·Minardi, S.·Faga, G.·Soffientini, P.·Allievi, E.·Cancila, V.·Bachi, A.·Fernandez-Capetillo, O.·Tripodo, C.·Ferrari, F.·Lopez-Contreras, A. J.·Costanzo, V.

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Abstract

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 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 GSRF1 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.

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Atashpaz, S., Samadi Shams, S., Gonzalez, J. M., Sebestyen, E., Arghavanifard, N., Gnocchi, A., Albers, E., Minardi, S., Faga, G., Soffientini, P., Allievi, E., Cancila, V., Bachi, A., Fernandez-Capetillo, O., Tripodo, C., Ferrari, F., Lopez-Contreras, A. J., Costanzo, V.. 2020-01-01. ATR expands embryonic stem cell fate potential in response to replication stress. https://doi.org/10.1101/2020.01.01.888354

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