Lnc956 regulates mouse embryonic stem cell differentiation in response to DNA damage in a p53-independent pathway

Maintaining genomic stability is crucial for embryonic stem cells (ESCs). ESCs with unrepaired DNA damage are eliminated through differentiation and apoptosis. To date, only tumor suppressor p53 is known to be implicated in this quality control process. Here, we identified a p53-independent quality...

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Bibliographic Details
Published in:Science advances 2023-01, Vol.9 (3), p.eade9742-eade9742
Main Authors: Ma, Huaixiao, Ning, Yuqi, Wang, Lin, Zhang, Weidao, Zheng, Ping
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cell Differentiation - genetics
Developmental Biology
DNA Damage
Gene Expression Regulation
Mice
Mouse Embryonic Stem Cells - metabolism
SciAdv r-articles
Stem Cells
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Maintaining genomic stability is crucial for embryonic stem cells (ESCs). ESCs with unrepaired DNA damage are eliminated through differentiation and apoptosis. To date, only tumor suppressor p53 is known to be implicated in this quality control process. Here, we identified a p53-independent quality control factor lncRNA NONMMUT028956 ( for short) in mouse ESCs. is prevalently expressed in ESCs and regulates the differentiation of ESCs after DNA damage. Mechanistically, Ataxia telangiectasia mutated (ATM) activation drives m A methylation of , which promotes its interaction with Krüppel-like factor 4 (KLF4). -KLF4 association sequestrates the KLF4 protein and prevents KLF4's transcriptional regulation on pluripotency. This posttranslational mechanism favors the rapid shutdown of the regulatory circuitry of pluripotency. Thus, ATM signaling in ESCs can activate two pathways mediated by p53 and , respectively, which act together to ensure robust differentiation and apoptosis in response to unrepaired DNA damage.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ade9742