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 control factor lncRNA NONMMUT028956 (Lnc956 for short) in mouse ESCs. Lnc956 is prevalently expressed in ESCs and regulates the differentiation of ESCs after DNA damage. Mechanistically, Ataxia telangiectasia mutated (ATM) activation drives m6A methylation of Lnc956, which promotes its interaction with Kruppel-like factor 4 (KLF4). Lnc956-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 Lnc956, respectively, which act together to ensure robust differentiation and apoptosis in response to unrepaired DNA damage.

Automated summary

Maintaining genomic stability is crucial for embryonic stem cells (ESCs). ESCs eliminate unrepaired DNA damage through differentiation and apoptosis, with tumor suppressor p53 known to be involved in this process. This study identified a p53-independent quality control factor called lncRNA NONMMUT028956 (Lnc956) in mouse ESCs. Lnc956 is abundantly expressed in ESCs and regulates ESC differentiation after DNA damage, promoting interaction with Kruppel-like factor 4 (KLF4). This interaction sequesters KLF4 and prevents its transcriptional regulation on pluripotency, favoring the shutdown of pluripotency regulatory circuitry. Additionally, ATM signaling in ESCs activates both the p53 and Lnc956 pathways to ensure robust differentiation and apoptosis in response to unrepaired DNA damage.