HGNC Approved Gene Symbol: PRMT6
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38): 1:107,056,674-107,059,294 (from NCBI)
Protein arginine N-methyltransferases, such as PRMT6, catalyze the sequential transfer of a methyl group from S-adenosyl-L-methionine to the side chain nitrogens of arginine residues within proteins to form methylated arginine derivatives and S-adenosyl-L-homocysteine.
By searching the genome for PRMT family members, followed by 5-prime RACE of a kidney cDNA library, Frankel et al. (2002) cloned PRMT6. The deduced 375-amino acid protein has a calculated molecular mass of 41.9 kD. PRMT6 contains a catalytic core sequence and no additional domains. The catalytic cores of PRMT6 and PRMT2 (601961) shares 38% amino acid identity. Northern blot analysis detected broad expression of 2.4- and 2.6-kb transcripts. Confocal microscopy of fluorescence-labeled PRMT6 showed strong nuclear localization in transfected HeLa cells.
Frankel et al. (2002) assayed the PRMT activity of recombinant PRMT6 overexpressed in E. coli. PRMT6 demonstrated type I PRMT activity, forming both omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives on a recombinant glycine- and arginine-rich substrate. There was an initial accumulation of the monomethyl species followed by accumulation of the final dimethylarginine product. A comparison of substrate specificities revealed that PRMT6 is functionally distinct from PRMT1 (602950) and PRMT4, which are also type I PRMTs. In addition, PRMT6 displayed automethylation activity.
El-Andaloussi et al. (2006) determined that human POLB (174760) formed a complex with and was methylated by PRMT6. In vitro, methylated POLB possessed significantly higher DNA polymerase activity when compared to that of unmodified enzyme. The increase in DNA polymerase activity upon methylation was due to the enhanced DNA binding and processivity of POLB.
Following up on the observation that asymmetric dimethylation of histone H3 (see 602810) arginine-2 (H3R2me2a) countercorrelates with di- and trimethylation of H3 lysine-4 (H3K4me2, H3K4me3) on human promoters, Guccione et al. (2007) demonstrated that the arginine methyltransferase PRMT6 catalyzes H3R2 dimethylation in vitro and controls global levels of H3R2me2a in vivo. H3R2 methylation by PRMT6 was prevented by the presence of H3K4me3 on the H3 tail. Conversely, the H3R2me2a mark prevented methylation of H3K4 as well as binding to the H3 tail by an ASH2 (604782)/WDR5 (609012)/MLL (159555) family methyltransferase complex. Chromatin immunoprecipitation showed that H3R2me2a was distributed within the body and at the 3-prime end of human genes, regardless of their transcriptional state, whereas it was selectively and locally depleted from active promoters, coincident with the presence of H3K4me3. Guccione et al. (2007) concluded that hence, the mutual antagonism between H3R2 and H3K4 methylation, together with the association of MLL family complexes with the basal transcription machinery, may contribute to the localized patterns of H3K4 trimethylation characteristic of transcriptionally poised or active promoters in mammalian genomes.
By genomic sequence analysis, Frankel et al. (2002) mapped the PRMT6 gene to chromosome 1.
Wolf (2009) reported that the PRMT6 gene maps to chromosome 1p13.3.
El-Andaloussi, N., Valovka, T., Toueille, M., Steinacher, R., Focke, F., Gehrig, P., Covic, M., Hassa, P. O., Schar, P., Hubscher, U., Hottiger, M. O. Arginine methylation regulates DNA polymerase beta. Molec. Cell 22: 51-62, 2006. [PubMed: 16600869] [Full Text: https://doi.org/10.1016/j.molcel.2006.02.013]
Frankel, A., Yadav, N., Lee, J., Branscombe, T. L., Clarke, S., Bedford, M. T. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J. Biol. Chem. 277: 3537-3543, 2002. [PubMed: 11724789] [Full Text: https://doi.org/10.1074/jbc.M108786200]
Guccione, E., Bassi, C., Casadio, F., Martinato, F., Cesaroni, M., Schuchlautz, H., Luscher, B., Amati, B. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449: 933-937, 2007. [PubMed: 17898714] [Full Text: https://doi.org/10.1038/nature06166]
Wolf, S. S. The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans. Cell. Molec. Life Sci. 66: 2109-2121, 2009. [PubMed: 19300908] [Full Text: https://doi.org/10.1007/s00018-009-0010-x]