RNA-Cap Methylation Essential for Embryonic Development

The Pillai lab investigated the roles of the mRNA cap methylases CMTR1 and CMTR2 which methylate the ribose of the first and second nucleotide of mRNAs thereby marking them as self and preventing the activation of the innate immune system. Deletion of either CMTR1 or CMTR2 results in embryonic lethality without triggering the innate immune response as no interfereon pathway activation can be seen. Also, different sets of transcripts are misregulated in either mutant. These results show that these methylases have further roles in gene regulation beyond shielding endogenous mRNAs from the innate immune system. Their findings have been published in the article "Essential roles of RNA cap-proximal ribose methylation in mammalian embryonic development and fertility"  in Cell Reports.


  • 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


Eukaryotic RNA pol II transcripts are capped at the 5' end by the methylated guanosine (m7G) 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.

Read the Publication in Cell Reports (Open Access)

Website Pillai Lab

Figure, highlights, summary and title from Dohnalkova et al (2023) Cell Rep published under a CC BY 4.0 license.