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 m(6)A methylation of Lnc956, which promotes its interaction with Krüppel-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.