Wyatt, Christopher Douglas Robert, 1988-Pernaute, BarbaraGohr, AndréMiret-Cuesta, MartaGoyeneche, LuciaRovira, QuirzeSalzer, Marion C.Boke, ElvanBogdanovic, OzrenBonnal, SophieIrimia Martínez, Manuel2022-06-012022-06-012022Wyatt CDR, Pernaute B, Gohr A, Miret-Cuesta M, Goyeneche L, Rovira Q et al. A developmentally programmed splicing failure contributes to DNA damage response attenuation during mammalian zygotic genome activation. Sci Adv. 2022 Apr 15;8(15):eabn4935. DOI:10.1126/sciadv.abn49352375-2548http://hdl.handle.net/10230/53342Transition from maternal to embryonic transcriptional control is crucial for embryogenesis. However, alternative splicing regulation during this process remains understudied. Using transcriptomic data from human, mouse, and cow preimplantation development, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Much of this exon skipping is temporary, leads to disruptive noncanonical isoforms, and occurs in genes enriched for DNA damage response in the three species. Two core spliceosomal components, Snrpb and Snrpd2, regulate these patterns. These genes have low maternal expression at ZGA and increase sharply thereafter. Microinjection of Snrpb/d2 messenger RNA into mouse zygotes reduces the levels of exon skipping at ZGA and leads to increased p53-mediated DNA damage response. We propose that mammalian embryos undergo an evolutionarily conserved, developmentally programmed splicing failure at ZGA that contributes to the attenuation of cellular responses to DNA damage.application/pdfeng© 2022 Christopher D. R. Wyatt et al. Some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly citedGenèticaGenòmicaEmbriologiainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.abn4935info:eu-repo/semantics/openAccess