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HGNC Approved Gene Symbol: RBM15
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38) : 1:110,339,377-110,346,677 (from NCBI)
Members of the SPEN (Split-end) family of proteins, including RBM15, have repressor function in several signaling pathways and may bind to RNA through interaction with spliceosome components (Hiriart et al., 2005).
Mercher et al. (2001) identified RBM15, which they called OTT, and determined that the deduced 957-amino acid protein contains 3 N-terminal RNA recognition motifs and a conserved C-terminal SPOC domain. RBM15 shares close homology with OTT3 (RBM15B; 612602) and human SPEN (also known as SHARP). Northern blot analysis of human tissues detected an 8.3-kb transcript with strong expression in heart, muscle, thymus, kidney, placenta, and peripheral blood leukocytes with weaker expression in brain, colon, spleen, liver, small intestine, and lung, and a 3.9-kb transcript with strong expression in muscle, spleen, and kidney.
Using mass spectrometric analysis to identify proteins that immunoprecipitated with WTAP (605442) from human umbilical vein endothelial cells (HUVECs), Horiuchi et al. (2013) identified a protein complex that included RBM15, HAKAI (CBLL1; 606872), virilizer (KIAA1429; 616447), ZC3H13 (616453), BCLAF1 (612588), and THRAP3 (603809). The WTAP complex localized to nuclear speckles in HeLa cells and HUVECs, and cross-linking experiments indicated that it transiently associated with splicing factors. Knockdown of any of the WTAP complex components, including RBM15, reduced alternative splicing of WTAP, resulting in increased production of the full-length WTAP protein, and reduced cell proliferation, with cell cycle arrest at G2 phase. Knockdown of both BCLAF1 and THRAP3 decreased nuclear speckle localization of other WTAP complex components.
Patil et al. (2016) demonstrated that, in human cells, XIST (314670) is highly methylated with at least 78 N6-methyladenosine (m6A) residues. No function for m6A in long noncoding RNAs had been demonstrated. Patil et al. (2016) showed that m6A formation in XIST, as well as in cellular mRNAs, is mediated by RBM15 and its paralog RBM15B, which bind the m6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m6A consensus motifs. Furthermore, Patil et al. (2016) showed that knockdown of RBM15 and RBM15B, or knockdown of METTL3 (612472), an m6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m6A-binding proteins shows that YTHDC1 preferentially recognizes m6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m6A. These data revealed a pathway of m6A formation and recognition required for XIST-mediated transcriptional repression.
Mercher et al. (2001) determined that the RBM15 gene contains 2 exons.
The RBM15 gene maps to chromosome 1p13 (Mercher et al., 2001; Ma et al., 2001).
The recurrent t(1;22)(p13;q13) translocation is exclusively associated with infantile acute megakaryoblastic leukemia (AMKL, FAB-M7). Mercher et al. (2001) and Ma et al. (2001) demonstrated that this chromosomal rearrangement results in a fusion of 2 genes. Both genes have homologous sequences in the Drosophila genome. The chromosome 22 gene (see 606078) was designated MAL by Mercher et al. (2001) and MKL1 by Ma et al. (2001). The chromosome 1 gene, which was referred to as RNA-binding motif protein-15 (RBM15) by Ma et al. (2001), was termed OTT (for 'one-twenty two') by Mercher et al. (2001). Structural analyses by Mercher et al. (2001) showed that the OTT promoter initiates transcription of a fusion RNA that would encode a fusion protein comprising almost all OTT and MAL products, whereas the reciprocal fusion transcript would code for a 17-amino acid peptide in the common translocation. The OTT-MAL product presented several features in common with the HRX fusions (159555), the other fusion frequently observed in infantile acute leukemias. Both fusion proteins are expected to participate in chromatin organization through the binding of AT-rich DNA sequences, recognized by the AT hook motif in HRX fusions and by the SAF (scaffold attachment factor) box in the OTT-MAL fusion.
Ma et al. (2001) found that although both reciprocal fusion transcripts are expressed in AMKL, the predicted RBM15-MKL1 chimeric protein encompasses all putative functional motifs encoded by each gene and is thus the candidate oncoprotein of t(1;22).
Mercher et al. (2002) reported 3 cases of acute megakaryocytic leukemia (M7) occurring in infants and showed that the RBM15-MKL1 fusion gene was present in all 5 t(1;22) cases that had been studied up to that time. Nucleotide sequence analysis of 2 translocation breakpoints suggested a nonhomologous end-joining mechanism in the genesis of this translocation and revealed a noncanonical topoisomerase II (126430)-like consensus sequence within the RBM15 gene. Mercher et al. (2002) suggested that the FISH and PCR techniques used in their study are useful for identifying t(1;22) associated with M7.
Raffel et al. (2009) stated that Ott1-null mouse embryos die around embryonic day 9.5. However, they found that death was likely due to a specific defect in early placental trophoblast development and placental vascular branching. A conditional knockout protocol that spared Ott1 deletion in trophoblasts rescued the placental phenotype and revealed a critical role for Ott1 in the development of heart, spleen, and vasculature. Conditional Ott1 -/- mice were obtained in close to a mendelian ratio, but they died within a few hours of birth. Mutant mice frequently showed pericardial effusion, a membranous ventricular septal defect, and hyposplenism with variable penetrance. Ott1 -/- embryos harvested at embryonic day 18.5 were often edematous, consistent with heart failure. Raffel et al. (2009) concluded that OTT1 is a critical factor in the development of tissues derived from mesoderm.
Hiriart, E., Gruffat, H., Buisson, M., Mikaelian, I., Keppler, S., Meresse, P., Mercher, T., Bernard, O. A., Sergeant, A., Manet, E. Interaction of the Epstein-Barr virus mRNA export factor EB2 with human Spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links Spen proteins with splicing regulation and mRNA export. J. Biol. Chem. 280: 36935-36945, 2005. [PubMed: 16129689] [Full Text: https://doi.org/10.1074/jbc.M501725200]
Horiuchi, K., Kawamura, T., Iwanari, H., Ohashi, R., Naito, M., Kodama, T., Hamakubo, T. Identification of Wilms' tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J. Biol. Chem. 288: 33292-33302, 2013. [PubMed: 24100041] [Full Text: https://doi.org/10.1074/jbc.M113.500397]
Ma, Z., Morris, S. W., Valentine, V., Li, M., Herbrick, J.-A., Cui, X., Bouman, D., Li, Y., Mehta, P. K., Nizetic, D., Kaneko, Y., Chan, G. C. F., Chan, L. C., Squire, J., Scherer, S. W., Hitzler, J. K. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genet. 28: 220-221, 2001. [PubMed: 11431691] [Full Text: https://doi.org/10.1038/90054]
Mercher, T., Busson-Le Coniat, M., Khac, F. N., Ballerini, P., Mauchauffe, M., Bui, H., Pellegrino, B., Radford, I., Valensi, F., Mugneret, F., Dastugue, N., Bernard, O. A., Berger, R. Recurrence of OTT-MAL fusin in t(1;22) of infant AML-M7. Genes Chromosomes Cancer 33: 22-28, 2002. [PubMed: 11746984] [Full Text: https://doi.org/10.1002/gcc.1208]
Mercher, T., Coniat, M. B.-L., Monni, R., Mauchauffe, M., Khac, F. N., Gressin, L., Mugneret, F., Leblanc, T., Dastugue, N., Berger, R., Bernard, O. A. Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc. Nat. Acad. Sci. 98: 5776-5779, 2001. [PubMed: 11344311] [Full Text: https://doi.org/10.1073/pnas.101001498]
Patil, D. P., Chen, C.-K., Pickering, B. F., Chow, A., Jackson, C., Guttman, M., Jaffrey, S. R. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537: 369-373, 2016. [PubMed: 27602518] [Full Text: https://doi.org/10.1038/nature19342]
Raffel, G. D., Chu, G. C., Jesneck, J. L., Cullen, D. E., Bronson, R. T., Bernard, O. A., Gilliland, D. G. Ott1 (Rbm15) is essential for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Molec. Cell. Biol. 29: 333-341, 2009. [PubMed: 18981216] [Full Text: https://doi.org/10.1128/MCB.00370-08]