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

Autor:	Atashpaz S; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Samadi Shams S; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Gonzalez JM; Transgenic Core Facility, University of Copenhagen, Copenhagen, Denmark., Sebestyén E; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Arghavanifard N; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy., Gnocchi A; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy., Albers E; Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark., Minardi S; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.; Cogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, Italy., Faga G; Experimental Therapeutics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Soffientini P; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Allievi E; Cogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, Italy., Cancila V; Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, Italy., Bachi A; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Fernández-Capetillo Ó; Spanish National Cancer Research Center, Madrid, Spain.; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Tripodo C; Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, Italy., Ferrari F; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., López-Contreras AJ; Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark., Costanzo V; IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy.; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Mar 12; Vol. 9. Date of Electronic Publication: 2020 Mar 12.
DOI:	10.7554/eLife.54756
Abstrakt:	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. Competing Interests: SA, SS, JG, ES, NA, AG, EA, SM, GF, PS, EA, VC, AB, ÓF, CT, FF, AL, VC No competing interests declared (© 2020, Atashpaz et al.)
Databáze:	MEDLINE
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