HGNC Approved Gene Symbol: MKRN1
Cytogenetic location: 7q34 Genomic coordinates (GRCh38): 7:140,453,033-140,479,569 (from NCBI)
The Makorin ring finger protein-1 gene (MKRN1) is a highly transcribed, intron-containing source for a family of intronless mammalian genes encoding a novel class of zinc finger proteins. Phylogenetic analyses indicate that the MKRN1 gene is the ancestral founder of this gene family (Gray et al., 2000).
Gray et al. (2000) cloned MKRN1 orthologs from human, mouse, wallaby, chicken, fruit fly, and nematode, underscoring the age and conservation of this gene. The human MKRN1 cDNA contains a contiguous sequence of 3,026 basepairs including an open reading frame (ORF) from nucleotide 121 to 1567 that encodes a putative protein of 482 amino acids. Mouse and Drosophila Mkrn1 proteins share 92% and 27% with the human protein, respectively, with Drosophila Mkrn1 reaching 63% identity over 123 amino acids spanning from upstream of the RING finger through the C-terminal C3H zinc finger. Northern blot analysis of human tissues detected a single prominent 3.2-kb transcript, suggesting that the MKRN1 gene is highly and uniformly expressed in all tissues, including different regions of the brain. High levels were observed in murine embryonic nervous system and adult testis.
Using a yeast 2-hybrid system, Kim et al. (2005) found that MKRN1 interacts with a C-terminal domain of TERT (187270), the catalytic subunit of the telomerase ribonucleoprotein. They demonstrated that MKRN1 functions as an E3 ubiquitin ligase, promoting TERT ubiquitination and proteasomal degradation. Mutation of his307 of MKRN1 or deletion of its C-terminal RING finger domain inactivated the enzyme. Overexpression of MKRN1 in telomerase-positive human cells decreased telomerase activity and reduced telomere length. Kim et al. (2005) concluded that MKRN1 plays a negative role in telomere homeostasis.
The MKRN gene family encodes putative ribonuclear proteins with a distinctive array of zinc finger motifs, including 2 to 4 C3H zinc fingers, an unusual cys/his arrangement that may represent a novel zinc finger structure, and a highly conserved RING zinc finger. Gray et al. (2000) provided a summary of 9 MKRN family loci distributed throughout the human genome.
The MKRN1 gene consists of 8 exons and spans approximately 28 kb (Gray et al., 2000).
By FISH and interspecific backcross analysis, respectively, Gray et al. (2000) determined that the human and mouse MKRN1 loci map to a conserved syntenic group proximal to the T-cell receptor-beta cluster (TCRB; see 186930) in chromosome 7q34-q35 in human and chromosome 6A in mouse.
Hirotsune et al. (2003) reported that transgenic disruption of a putative pseudogene, Mkrn1-p1, resulted in destabilization of Mkrn1 mRNA in trans and generated a phenotype with polycystic kidneys and bone deformity. Gray et al. (2006) were unable to replicate the findings of Hirotsune et al. (2003). They showed that 5-prime Mkrn1-p1 is fully methylated on both alleles, indicative of silenced chromatin, and that Mkrn1-p1 is not transcribed and therefore cannot stabilize Mkrn1 transcripts in trans. They determined that the putative Mkrn1-p1 reported by Hirotsune et al. (2003) is actually a short splice variant of the Mkrn1 gene. Mice in which Mkrn1 had been directly disrupted showed none of the phenotypes attributed by Hirotsune et al. (2003) to a partial reduction of an Mkrn1 isoform. In addition, Gray et al. (2006) found that Mkrn1-p1 appeared specific to mouse; it was not found in any other species, including rat.
Gray, T. A., Hernandez, L., Carey, A. H., Schaldach, M. A., Smithwick, M. J., Rus, K., Graves, J. A. M., Stewart, C. L., Nicholls, R. D. The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system. Genomics 66: 76-86, 2000. [PubMed: 10843807] [Full Text: https://doi.org/10.1006/geno.2000.6199]
Gray, T. A., Wilson, A., Fortin, P. J., Nicholls, R. D. The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans. Proc. Nat. Acad. Sci. 103: 12039-12044, 2006. [PubMed: 16882727] [Full Text: https://doi.org/10.1073/pnas.0602216103]
Hirotsune, S., Yoshida, N., Chen, A., Garrett, L., Sugiyama, F., Takahashi, S., Yagami, K., Wynshaw-Boris, A., Yoshiki, A. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Nature 423: 91-96, 2003. Note: Addendum: Nature 426: 100 only, 2003. [PubMed: 12721631] [Full Text: https://doi.org/10.1038/nature01535]
Kim, J. H., Park, S.-M., Kang, M. R., Oh, S.-Y., Lee, T. H., Muller, M. T., Chung, I. K. Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. Gene Dev. 19: 776-781, 2005. [PubMed: 15805468] [Full Text: https://doi.org/10.1101/gad.1289405]