TUT1-catalyzed U6 snRNA 3′-end maturation is required for mRNA splicing to maintain stem cell pools during embryogenesis [RNA-Seq]

The post-transcriptional maturation of U6 snRNA 3′-end is important for spliceosomal assembly and RNA splicing, and is catalyzed by sequential enzymatic activities of TUT1 and USB1, that is, an oligo(U) tail is first added by TUT1 to the freshly transcribed U6 snRNA, and then trimmed by USB1 to generate mature U6 snRNA. However, biallelic inactivation of TUT1 or USB1 is linked to distinct human developmental disorders, and their physiological functions remain unknown.

Here, using multiple genetically engineered mouse models, we show that Tut1, but unexpectedly not Usb1, is essential for the maintenance of the epiblast and neural stem cells in vivo. Loss of Tut1 weakens the interactions between essential splicing factors and U6 snRNA, causes defective RNA splicing, and triggers massive DNA damage and subsequent cell death. Importantly, cell death can be prevented by recombinant U6 snRNA containing an oligo(U) tail.