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

被引:42
作者
Atashpaz, Sina [1 ]
Shams, Sara Samadi [1 ]
Gonzalez, Javier Martin [2 ]
Sebestyen, Endre [1 ]
Arghavanifard, Negar [1 ,3 ]
Gnocchi, Andrea [1 ,3 ]
Albers, Eliene [4 ,5 ]
Minardi, Simone [1 ,6 ]
Faga, Giovanni [7 ]
Soffientini, Paolo [1 ]
Allievi, Elisa [6 ]
Cancila, Valeria [8 ]
Bachi, Angela [1 ]
Fernandez-Capetillo, Oscar [9 ,10 ]
Tripodo, Claudio [8 ]
Ferrari, Francesco [1 ]
Lopez-Contreras, Andres Joaquin [4 ,5 ]
Costanzo, Vincenzo [1 ,3 ]
机构
[1] IFOM FIRC Inst Mol Oncol, Milan, Italy
[2] Univ Copenhagen, Transgen Core Facil, Copenhagen, Denmark
[3] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy
[4] Univ Copenhagen, Ctr Chromosome Stabil, Copenhagen, Denmark
[5] Univ Copenhagen, Ctr Hlth Aging, Dept Cellular & Mol Med, Copenhagen, Denmark
[6] IFOM FIRC Inst Mol Oncol Milan, Cogentech, Milan, Italy
[7] IFOM FIRC Inst Mol Oncol, Expt Therapeut Program, Milan, Italy
[8] Univ Palermo, Dept Hlth Sci, Tumor Immunol Unit, Human Pathol Sect,Sch Med Palermo, Palermo, Italy
[9] Spanish Natl Canc Res Ctr, Madrid, Spain
[10] Karolinska Inst, Dept Med Biochem & Biophys, Div Genome Biol, Sci Life Lab, Stockholm, Sweden
来源
ELIFE | 2020年 / 9卷
基金
欧洲研究理事会; 新加坡国家研究基金会;
关键词
DNA-DAMAGE; EPIGENETIC RESTRICTION; TELOMERE ELONGATION; STATISTICAL-MODEL; GENOMIC STABILITY; GENE ATR; KINASE; EXPRESSION; ZSCAN4; LEADS;
D O I
10.7554/eLife.54756
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:30
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