The nonsense-mediated mRNA decay (NMD) pathway safeguards telomeres in pluripotent stem cells

Telomeres are repetitive DNA sequences that cap chromosome ends and are bound by the Shelterin complex to prevent aberrant activation of DNA damage signaling. While TRF2, a core Shelterin component, is essential for repressing non-homologous end joining (NHEJ) in somatic cells, it is dispensable for telomere protection in mouse embryonic stem cells (mESCs). To uncover compensatory pathways, we performed a synthetic lethal genome-wide CRISPR/Cas9 screen in TRF2-deficient mESCs and identified multiple components of the nonsense-mediated mRNA decay (NMD) pathway as essential for cell viability. We show that NMD promotes telomere protection by regulating the abundance of TRF1, another Shelterin component, at telomeres. Specifically, NMD limits the accumulation of a TRF1 mRNA isoform that encodes a dominant-negative protein variant. These findings reveal a previously unrecognized role for mRNA surveillance in maintaining telomere integrity in pluripotent cells. Overall design: RNA-seq profiling of control Trf2f/f mouse embryonic stem cells and sub-lines containing Smg5-/-, Smg6-/-, and Upf1HM alleles.