Cmtr2, also known as HMTR2, is an mRNA cap methyltransferase. It catalyzes 2'-O-ribose methylation of the second transcribed nucleotide of mRNAs, marking RNAs as "self" to avoid the cellular innate immune response. This function is associated with the innate immune pathway and is of great biological importance in mammalian cells [1,2,4,5,6]. Genetic models, especially KO/CKO mouse models, are valuable for studying Cmtr2.

Constitutive deletion of Cmtr2 in mice leads to mid-gestation embryonic death, with defects in embryo size, placental malformation, and yolk sac vascularization. Endothelial cell-specific deletion results in vascular and hematopoietic defects, as well as perinatal lethality. The constitutive Cmtr2 KO phenotype shows activation of the p53 pathway and decreased proliferation, without interferon pathway activation [1]. In addition, loss of mouse Cmtr2 leads to embryonic lethality, with misregulated transcripts but no interferon pathway activation [2].

In conclusion, Cmtr2 is essential for mammalian embryonic development, as revealed by KO/CKO mouse models. These models also suggest its potential involvement in diseases like lung cancer and cutaneous melanoma, as rare variants in Cmtr2 are associated with an increased risk of these cancers [1,2,3].

References:

1. Yermalovich, Alena V, Mohsenin, Zarin, Cowdin, Mitzy, Cleaver, Ondine, Meyerson, Matthew. 2024. An essential role for Cmtr2 in mammalian embryonic development. In Developmental biology, 516, 47-58. doi:10.1016/j.ydbio.2024.07.019. https://pubmed.ncbi.nlm.nih.gov/39094818/

2. Dohnalkova, Michaela, Krasnykov, Kyrylo, Mendel, Mateusz, Homolka, David, Pillai, Ramesh S. 2023. Essential roles of RNA cap-proximal ribose methylation in mammalian embryonic development and fertility. In Cell reports, 42, 112786. doi:10.1016/j.celrep.2023.112786. https://pubmed.ncbi.nlm.nih.gov/37436893/

3. Ivarsdottir, Erna V, Gudmundsson, Julius, Tragante, Vinicius, Gudbjartsson, Daniel F, Stefansson, Kari. 2024. Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. In Nature genetics, 56, 2422-2433. doi:10.1038/s41588-024-01966-6. https://pubmed.ncbi.nlm.nih.gov/39472694/

4. Avila-Bonilla, Rodolfo Gamaliel, Macias, Sara. 2024. The molecular language of RNA 5' ends: guardians of RNA identity and immunity. In RNA (New York, N.Y.), 30, 327-336. doi:10.1261/rna.079942.124. https://pubmed.ncbi.nlm.nih.gov/38325897/

5. Smietanski, Miroslaw, Werner, Maria, Purta, Elzbieta, Nowotny, Marcin, Bujnicki, Janusz M. . Structural analysis of human 2'-O-ribose methyltransferases involved in mRNA cap structure formation. In Nature communications, 5, 3004. doi:10.1038/ncomms4004. https://pubmed.ncbi.nlm.nih.gov/24402442/

6. Werner, Maria, Purta, Elzbieta, Kaminska, Katarzyna H, Jaworski, Jacek, Bujnicki, Janusz M. 2011. 2'-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family. In Nucleic acids research, 39, 4756-68. doi:10.1093/nar/gkr038. https://pubmed.ncbi.nlm.nih.gov/21310715/