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

被引：47

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

页数：30

共 72 条

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