Alternative titles; symbols
HGNC Approved Gene Symbol: DXO
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38) : 6:31,969,815-31,972,138 (from NCBI)
The major histocompatibility complex (MHC, also known as HLA) complement gene cluster varies in size from 142 to 214 kb and contains many polymorphic genes located between the complement component-2 gene (C2; 613927) and the extracellular matrix tenascin X gene (see 600985) on chromosome 6p21.3 (see Yu (1998) for review). By genomic sequence analysis, EST database searching, and 5-prime-RACE, Yang et al. (1998) obtained a full-length cDNA encoding DOM3Z, which is located within the MHC complement gene cluster. Sequence analysis predicted that the 396-amino acid protein is 12% proline and has 4 potential N-myristoylation sites, multiple potential phosphorylation sites, and a leucine zipper motif. The DOM3Z protein is conserved in simple and complex eukaryotes. Northern blot analysis revealed that like STK19 (604977) and RD (154040), DOM3Z is ubiquitously expressed. DOM3Z was expressed predominantly as a 1.5-kb transcript, with highest levels in testis and lowest levels in lung.
Xue et al. (2000) showed that S. cerevisiae Rai1, a homolog of human DOM3Z, bound to and enhanced the activity of Rat1 (XRN2; 608851) in vivo and in vitro and was required for normal 5.8S ribosomal RNA processing.
Jiao et al. (2009) reported that the yeast Rai1 protein has pyrophosphohydrolase activity towards mRNAs lacking a 5-prime-end cap. Jiao et al. (2010) showed that, in vitro as well as in yeast cells, Rai1 possesses a novel decapping endonuclease activity that can also remove the entire cap structure dinucleotide from an mRNA. This activity is targeted preferentially towards mRNAs with unmethylated caps in contrast to the canonical decapping enzyme Dcp2 (609844), which targets mRNAs with a methylated cap. Capped but unmethylated mRNAs generated in yeast cells with a defect in the methyltransferase gene were more stable in a Rai1 gene-disrupted background. Moreover, Rai1-deleted yeast cells with wildtype capping enzymes showed significant accumulation of mRNAs with 5-prime end capping defects under nutritional stress conditions of glucose starvation or amino acid starvation. Jiao et al. (2010) concluded that their findings provided evidence that 5-prime-end capping is not a constitutive process that necessarily always proceeds to completion and demonstrated that Rai1 has an essential role in clearing mRNAs with aberrant 5-prime-end caps. Jiao et al. (2010) proposed that Rai1 is involved in a quality control process that ensures mRNA 5-prime-end integrity by an aberrant cap-mediated mRNA decay mechanism.
Xiang et al. (2009) reported the crystal structure at 2.2-angstrom resolution of S. pombe Rat1 in complex with Rai1, as well as the structure of Rai1 and its murine homolog Dom3Z alone at 2.0-angstrom resolution. The structures revealed the molecular mechanism for the activation of Rat1 by Rai1 and for the exclusive exoribonuclease activity of Rat1. Biochemical studies confirmed these observations, and showed that Rai1 allows Rat1 to degrade RNAs with stable secondary structure more effectively. There are large differences in the active site landscape of Rat1 compared to related and PIN (PilT N terminus) domain-containing nucleases. Unexpectedly, Xiang et al. (2009) identified a large pocket in Rai1 and Dom3Z that contains highly conserved residues, including 3 acidic side chains that coordinate a divalent cation. Mutagenesis and biochemical studies demonstrated that Rai1 possesses pyrophosphohydrolase activity towards 5-prime triphosphorylated RNA. Such an activity is important for mRNA degradation in bacteria, but this was thought to be the first demonstration of this activity in eukaryotes, and suggested that Rai1/Dom3Z may have additional important functions in RNA metabolism.
Yang et al. (1998) determined that the DOM3Z gene has a GC-rich promoter region and contains 7 exons. Yang et al. (1998) proposed that the structural similarities and tight linkage of the RD, SKIV2L (600478), DOM3Z, and STK19 genes may imply concerted functions, such as in RNA splicing, and may help elucidate the molecular basis of disease associations with the HLA complement gene cluster.
By genomic sequence analysis, Yang et al. (1998) determined that the DOM3Z gene maps to the HLA class III region on 6p21.3, between the STK19 and SKIV2L (600478) genes in head-to-head and tail to-tail configurations, respectively.
Jiao, X., Chen, H., Chen, J., Herrup, K., Firestein, B. L., Kiledjian, M. Modulation of neuritogenesis by a protein implicated in X-linked mental retardation. J. Neurosci. 29: 12419-12427, 2009. [PubMed: 19812318] [Full Text: https://doi.org/10.1523/JNEUROSCI.5954-08.2009]
Jiao, X., Xiang, S., Oh, C., Martin, C. E., Tong, L., Kiledjian, M. Identification of a quality-control mechanism for mRNA 5-prime-end capping. Nature 467: 608-611, 2010. [PubMed: 20802481] [Full Text: https://doi.org/10.1038/nature09338]
Xiang, S., Cooper-Morgan, A., Jiao, X., Kiledjian, M., Manley, J. L., Tong, L. Structure and function of the 5-prime to 3-prime exoribonucleases Rat1 and its activating partner Rai1. Nature 458: 784-788, 2009. [PubMed: 19194460] [Full Text: https://doi.org/10.1038/nature07731]
Xue, Y., Bai, X., Lee, I., Kallstrom, G., Ho, J., Brown, J., Stevens, A., Johnson, A. W. Saccharomyces cerevisiae RAI1 (YGL246c) is homologous to human DOM3Z and encodes a protein that binds the nuclear exoribonuclease Rat1p. Molec. Cell. Biol. 20: 4006-4015, 2000. [PubMed: 10805743] [Full Text: https://doi.org/10.1128/MCB.20.11.4006-4015.2000]
Yang, Z., Shen, L., Dangel, A. W., Wu, L.-C., Yu, C. Y. Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 53: 338-347, 1998. [PubMed: 9799600] [Full Text: https://doi.org/10.1006/geno.1998.5499]
Yu, C. Y. Molecular genetics of the human MHC complement gene cluster. Exp. Clin. Immunogenet. 15: 213-230, 1998. [PubMed: 10072631] [Full Text: https://doi.org/10.1159/000019075]