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ATR expands embryonic stem cell fate potential in response to replication stress
Sina Atashpaz1, Sara Samadi Shams1, Javier Martin Gonzalez2
1IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.
Elife
|March 13, 2020
Summary
A novel ATR pathway controls embryonic genome stability by activating DUX, which induces totipotent genes in response to replication stress. This maintains DNA integrity and expands embryonic stem cell fate potential.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- Unrepaired DNA damage in early development can affect many cells.
- Mechanisms controlling damaged cells in embryos are not well understood.
Purpose of the Study:
- To investigate the transcriptional response to replication stress in mouse embryonic stem cells (ESCs).
- To identify the role of ATR-CHK1 pathway and DUX in maintaining genome stability during embryonic development.
Main Methods:
- Analysis of ATR- and CHK1-mediated transcriptional response in mouse ESCs.
- Investigated the role of DUX in regulating 2C-like genes (MERVL, Zscan4).
- Studied ATR activation via ETAA1 and its effect on DUX mRNA regulation by GRSF1.
Main Results:
- Replication stress induces an ATR-CHK1-DUX pathway activating totipotent 2C-like genes.
- ETAA1-mediated ATR activation also triggers this response.
- GRSF1 regulates DUX mRNA post-transcriptionally for ATR-mediated activation.
- ATR activation expands ESCs' developmental potential to embryonic and extra-embryonic tissues.
Conclusions:
- A novel ATR-dependent pathway maintains genome stability in developing embryos.
- This pathway controls ESCs fate by regulating DUX in response to replication stress.
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