ATR expands embryonic stem cell fate potential in response to replication stress
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 transcr...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/54756 |
| _version_ | 1811202955181817856 |
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| author | Sina Atashpaz Sara Samadi Shams Javier Martin Gonzalez Endre Sebestyén Negar Arghavanifard Andrea Gnocchi Eliene Albers Simone Minardi Giovanni Faga Paolo Soffientini Elisa Allievi Valeria Cancila Angela Bachi Óscar Fernández-Capetillo Claudio Tripodo Francesco Ferrari Andrés Joaquin López-Contreras Vincenzo Costanzo |
| author_facet | Sina Atashpaz Sara Samadi Shams Javier Martin Gonzalez Endre Sebestyén Negar Arghavanifard Andrea Gnocchi Eliene Albers Simone Minardi Giovanni Faga Paolo Soffientini Elisa Allievi Valeria Cancila Angela Bachi Óscar Fernández-Capetillo Claudio Tripodo Francesco Ferrari Andrés Joaquin López-Contreras Vincenzo Costanzo |
| author_sort | Sina Atashpaz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:46:23Z |
| format | Article |
| id | doaj.art-91525f93557a4ea295fba0e2fcd0a4fa |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:46:23Z |
| publishDate | 2020-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-91525f93557a4ea295fba0e2fcd0a4fa2022-12-22T03:51:09ZengeLife Sciences Publications LtdeLife2050-084X2020-03-01910.7554/eLife.54756ATR expands embryonic stem cell fate potential in response to replication stressSina Atashpaz0https://orcid.org/0000-0003-0566-5629Sara Samadi Shams1https://orcid.org/0000-0002-1697-9343Javier Martin Gonzalez2https://orcid.org/0000-0002-7075-6028Endre Sebestyén3https://orcid.org/0000-0001-5470-2161Negar Arghavanifard4https://orcid.org/0000-0003-3039-7603Andrea Gnocchi5https://orcid.org/0000-0003-3290-9449Eliene Albers6Simone Minardi7https://orcid.org/0000-0001-7303-3821Giovanni Faga8Paolo Soffientini9Elisa Allievi10Valeria Cancila11Angela Bachi12Óscar Fernández-Capetillo13Claudio Tripodo14Francesco Ferrari15Andrés Joaquin López-Contreras16Vincenzo Costanzo17https://orcid.org/0000-0002-2920-9508IFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyTransgenic Core Facility, University of Copenhagen, Copenhagen, DenmarkIFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, ItalyCenter for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DenmarkIFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Cogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, ItalyExperimental Therapeutics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyCogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, ItalyTumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, ItalySpanish National Cancer Research Center, Madrid, Spain; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, SwedenTumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, ItalyIFOM-The FIRC Institute of Molecular Oncology, Milan, ItalyCenter for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DenmarkIFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, ItalyUnrepaired 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.https://elifesciences.org/articles/54756ATRembryonic stem cellreplication stress |
| spellingShingle | Sina Atashpaz Sara Samadi Shams Javier Martin Gonzalez Endre Sebestyén Negar Arghavanifard Andrea Gnocchi Eliene Albers Simone Minardi Giovanni Faga Paolo Soffientini Elisa Allievi Valeria Cancila Angela Bachi Óscar Fernández-Capetillo Claudio Tripodo Francesco Ferrari Andrés Joaquin López-Contreras Vincenzo Costanzo ATR expands embryonic stem cell fate potential in response to replication stress eLife ATR embryonic stem cell replication stress |
| title | ATR expands embryonic stem cell fate potential in response to replication stress |
| title_full | ATR expands embryonic stem cell fate potential in response to replication stress |
| title_fullStr | ATR expands embryonic stem cell fate potential in response to replication stress |
| title_full_unstemmed | ATR expands embryonic stem cell fate potential in response to replication stress |
| title_short | ATR expands embryonic stem cell fate potential in response to replication stress |
| title_sort | atr expands embryonic stem cell fate potential in response to replication stress |
| topic | ATR embryonic stem cell replication stress |
| url | https://elifesciences.org/articles/54756 |
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