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ATR expands embryonic stem cell fate potential in response to replication stress.
- Source :
-
ELife [Elife] 2020 Mar 12; Vol. 9. Date of Electronic Publication: 2020 Mar 12. - Publication Year :
- 2020
-
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 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.<br />Competing Interests: SA, SS, JG, ES, NA, AG, EA, SM, GF, PS, EA, VC, AB, ÓF, CT, FF, AL, VC No competing interests declared<br /> (© 2020, Atashpaz et al.)
- Subjects :
- Animals
Ataxia Telangiectasia Mutated Proteins genetics
Ataxia Telangiectasia Mutated Proteins metabolism
Cell Differentiation
Cell Proliferation physiology
Cells, Cultured
Checkpoint Kinase 1 genetics
Chimera
Chromatography, Liquid
Cloning, Molecular
DNA Damage
Embryonic Stem Cells
Gene Expression Regulation
Mice
RNA, Messenger genetics
RNA, Messenger metabolism
Sequence Analysis, RNA
Tandem Mass Spectrometry
Checkpoint Kinase 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 32163370
- Full Text :
- https://doi.org/10.7554/eLife.54756