1. Essential roles of RNA cap-proximal ribose methylation in mammalian embryonic development and fertility.
- Author
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Dohnalkova, Michaela, Krasnykov, Kyrylo, Mendel, Mateusz, Li, Lingyun, Panasenko, Olesya, Fleury-Olela, Fabienne, Vågbø, Cathrine Broberg, Homolka, David, and Pillai, Ramesh S.
- Abstract
Eukaryotic RNA pol II transcripts are capped at the 5′ end by the methylated guanosine (m
7 G) moiety. In higher eukaryotes, CMTR1 and CMTR2 catalyze cap-proximal ribose methylations on the first (cap1) and second (cap2) nucleotides, respectively. These modifications mark RNAs as "self," blocking the activation of the innate immune response pathway. Here, we show that loss of mouse Cmtr1 or Cmtr2 leads to embryonic lethality, with non-overlapping sets of transcripts being misregulated, but without activation of the interferon pathway. In contrast, Cmtr1 mutant adult mouse livers exhibit chronic activation of the interferon pathway, with multiple interferon-stimulated genes being expressed. Conditional deletion of Cmtr1 in the germline leads to infertility, while global translation is unaffected in the Cmtr1 mutant mouse liver and human cells. Thus, mammalian cap1 and cap2 modifications have essential roles in gene regulation beyond their role in helping cellular transcripts to evade the innate immune system. [Display omitted] • CMTR1 and CMTR2 are essential for mouse embryonic development • Absence of interferon pathway activation in arrested mutant mouse embryos • Chronic activation of the interferon pathway in Cmtr1 mutant livers • Conditional loss of Cmtr1 in the mouse germline leads to infertility Mammalian RNA cap-proximal ribose methylations are implicated in preventing the activation of the interferon pathway. Dohnalkova et al. reveal that loss of the mouse RNA methylases CMTR1 and CMTR2 causes embryonic developmental arrest without activation of the interferon pathway, pointing to gene regulatory roles. [ABSTRACT FROM AUTHOR]- Published
- 2023
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