ATR expands embryonic stem cell fate potential in response to replication stress
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ATR expands embryonic stem cell fate potential in response to replication stress. / Atashpaz, Sina; Samadi Shams, Sara; Gonzalez, Javier Martin; Sebestyén, Endre; Arghavanifard, Negar; Gnocchi, Andrea; Albers, Eliene; Minardi, Simone; Faga, Giovanni; Soffientini, Paolo; Allievi, Elisa; Cancila, Valeria; Bachi, Angela; Fernández-Capetillo, Óscar; Tripodo, Claudio; Ferrari, Francesco; López-Contreras, Andrés Joaquin; Costanzo, Vincenzo.
In: eLife, Vol. 9, e54756, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - ATR expands embryonic stem cell fate potential in response to replication stress
AU - Atashpaz, Sina
AU - Samadi Shams, Sara
AU - Gonzalez, Javier Martin
AU - Sebestyén, Endre
AU - Arghavanifard, Negar
AU - Gnocchi, Andrea
AU - Albers, Eliene
AU - Minardi, Simone
AU - Faga, Giovanni
AU - Soffientini, Paolo
AU - Allievi, Elisa
AU - Cancila, Valeria
AU - Bachi, Angela
AU - Fernández-Capetillo, Óscar
AU - Tripodo, Claudio
AU - Ferrari, Francesco
AU - López-Contreras, Andrés Joaquin
AU - Costanzo, Vincenzo
N1 - © 2020, Atashpaz et al.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.7554/eLife.54756
DO - 10.7554/eLife.54756
M3 - Journal article
C2 - 32163370
VL - 9
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e54756
ER -
ID: 238950112