IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
Eliene Albers
Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy; Cogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, Italy
Giovanni Faga
Experimental Therapeutics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
Paolo Soffientini
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
Elisa Allievi
Cogentech, IFOM-The FIRC Institute of Molecular Oncology Milan, Milan, Italy
Valeria Cancila
Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, Italy
Angela Bachi
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
Óscar Fernández-Capetillo
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
Claudio Tripodo
Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, University of Palermo School of Medicine Palermo, Palermo, Italy
Francesco Ferrari
IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
Andrés Joaquin López-Contreras
Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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.
