Nonsense-mediated mRNA decay safeguards telomeres in pluripotent stem cells

Telomeres are protective DNA caps at chromosome ends that prevent cells from mistakenly recognizing them as broken DNA. These structures are safeguarded by a protein complex called Shelterin, particularly through the TRF2 protein encoded by Trf2. Surprisingly, in mouse embryonic stem cells, TRF2 is not essential for telomere protection, suggesting that other mechanisms compensate for its loss. Here we show that a cellular quality control system called nonsense-mediated mRNA decay (NMD), which normally eliminates defective RNA molecules, plays an unexpected role in maintaining telomere integrity in pluripotent cells. Through a genome-wide genetic screen, we discovered that NMD is essential for cell survival when TRF2 is absent. NMD accomplishes this by degrading an aberrant form of the messenger RNA encoded by Trf1, which produces the TRF1 protein, another Shelterin component. Without NMD, this aberrant RNA produces a truncated, harmful version of TRF1 that interferes with normal telomere protection. Our findings reveal that embryonic stem cells use a unique strategy for chromosome end protection, linking RNA quality control to genome stability in a previously unrecognized way.