Alternative titles; symbols
HGNC Approved Gene Symbol: PRMT1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:49,676,153-49,688,447 (from NCBI)
PRMT1, which catalyzes the formation of monomethylarginine and asymmetric dimethylarginine, is involved in a variety of processes, including gene transcription, DNA repair, and signal transduction (review by Wolf, 2009).
Protein arginine methylation is catalyzed by arginine methyltransferases. The bulk of methylated arginine residues in eukaryotic cells are found in heterogeneous nuclear ribonucleoproteins (hnRNPs), RNA-binding proteins that play essential roles in the metabolism of nuclear pre-mRNA. Lin et al. (1996) identified a rat cDNA encoding PRMT1 (protein-arginine N-methyltransferase 1; EC 2.1.1.23). Recombinant PRMT1 methylated histones and hnRNPA1 (164017) in vitro. By using a yeast 2-hybrid screen to identify proteins that interact with the intracytoplasmic domain of the interferon-alpha/beta receptor-1 (IFNAR1; 107450), Abramovich et al. (1997) identified a human cDNA encoding a protein that was nearly identical to PRMT1. The deduced 361-amino acid protein was designated IR1B4 for 'interferon receptor-1-bound protein 4.' Epitope-tagged IR1B4 bound the IFNAR1 intracytoplasmic domain in vitro. Antibodies against IFNAR1 coimmunoprecipitated a methyltransferase activity from human cell extracts. An antisense oligonucleotide strongly reduced methyltransferase activity in human cells, and caused them to become more resistant to growth inhibition by interferon. Abramovich et al. (1997) concluded that protein methylation, like phosphorylation, may be an important signaling mechanism for certain cytokine receptors.
Scott et al. (1998) identified HRMT1L2 transcripts with variable 5-prime ends that encode 3 protein variants with different N-terminal regions. Rat PRMT1 and HRMT1L2 variant 2 (v2) share 95% sequence identity, but diverge at their N termini. The amino acid sequences of HRMT1L2 and HRMT1L1 (601961) are 27% identical. Recombinant protein methylated human hnRNPA1 and a yeast hnRNP in vitro. The HRMT1L2 gene complemented mutations in the yeast hnRNP methyltransferase gene HMT1. Northern blot analysis revealed that HRMT1L2 is expressed as a predominant 1.4-kb mRNA in various adult and fetal tissues. Additional larger and smaller bands were observed in some tissues.
Scorilas et al. (2000) identified 3 splice variants of PRMT1, encoding deduced polypeptides of 343 (variant 1), 361 (variant 2), and 347 (variant 3) amino acids with molecular masses of 39.6, 41.5, and 39.9 kD, respectively. The full-length protein (v3) contains an in-frame stop codon in the middle of exon 3, and a second downstream start codon that resumes transcription. Variant 2 is predicted to contain 3 hydrophobic stretches, one of which may be a signal peptide. PRMT1 shares 96%, 34% and 29% sequence identity with rat PRMT1, human PRMT3 (603190), and human PRMT2 (HRMT1L1), respectively. RT-PCR revealed ubiquitous expression of all 3 splice variants, with highest expression in cerebellum, mammary gland, prostate, brain, and thyroid. The predominant variant differed among tissues. By PCR analysis, Scorilas et al. (2000) found that variants 1 and 2 were frequently downregulated in breast cancers in comparison to normal breast tissue.
In his review, Wolf (2009) noted that most isoforms of PRMT1 localize to the nucleus.
The S. cerevisiae ire15 mutation has an inositol auxotrophic phenotype and a defect in the expression of the inositol 1-phosphate synthase (INO1) gene. Nikawa et al. (1996) identified HRMT1L2, which they called HCP1, as a gene that suppressed the ire15 mutation. Multicopy HRMT1L2 increased the level of INO1 mRNA in ire15 mutants. Both Abramovich et al. (1997) and Scott et al. (1998) noted that the nucleotide sequence reported by Nikawa et al. (1996) contained 3 deletions that resulted in a frameshift between amino acids 147-175.
Wang et al. (2001) reported the purification, molecular identification, and functional characterization of the histone H4-specific methyltransferase PRMT1, a protein arginine methyltransferase. PRMT1 specifically methylates arginine-3 of histone H4 (see 602822) in vitro and in vivo. Methylation of arg3 by PRMT1 facilitates subsequent acetylation of H4 tails by p300 (602700). However, acetylation of H4 inhibits its methylation by PRMT1. Most important, a mutation in the S-adenosyl-L-methionine-binding site of PRMT1 substantially crippled its nuclear receptor coactivator activity. Wang et al. (2001) concluded that their findings reveal arg3 of H4 as a novel methylation site by PRMT1 and indicate that arg3 methylation plays an important role in transcriptional regulation.
Mowen et al. (2001) demonstrated that methylation of arg31 of STAT1 (600555) by PRMT1 is required for transcription induced by IFN-alpha/IFN-beta. They concluded that arginine methylation of STAT1 is an additional posttranslational modification regulating transcription factor function, and alteration of arginine methylation might be responsible for the lack of interferon responsiveness observed in many malignancies.
Using systems reconstituted with recombinant chromatin templates and coactivators, An et al. (2004) demonstrated the involvement of PRMT1 and CARM1 (603934) in p53 (191170) function; both independent and ordered cooperative functions of p300 (602700), PRMT1, and CARM1; and mechanisms involving direct interactions with p53 and obligatory modifications of corresponding histone substrates. Chromatin immunoprecipitation analyses confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on a p53-responsive gene, GADD45 (126335), following ectopic p53 expression and/or ultraviolet irradiation.
Scorilas et al. (2000) determined that the PRMT1 gene (variant 3) contains 12 exons and spans 11.2 kb, and that the 2 additional splice variants contain 10 (variant 1) or 11 exons (variant 2). They found that PRMT1 is located in close proximity to the IRF3 (603734) and RRAS (165090) genes and is transcribed in the opposite direction. RRAS is the most telomeric, followed by IRF3 and PRMT1.
By analysis of somatic cell hybrid panels and by fluorescence in situ hybridization, Scott et al. (1998) mapped the HRMT1L2 gene to 19q13. Noting sequence identity between HRMT1L2 and a BAC clone, Scorilas et al. (2000) refined the mapping to 19q13.3.
Pawlak et al. (2000) mapped the mouse Prmt1 gene to chromosome 7 by interspecific backcross analysis.
Pawlak et al. (2000) characterized a null mutation of the mouse Prmt1 gene, which is 95% identical to HRMT1L2. Prmt1 expression was greatest along the midline of the neural plate and in the forming head fold from embryonic day 7.5 (E7.5) to E8.5 and in the developing central nervous system from E8.5 to E13.5. Homozygous mutant embryos failed to develop beyond E6.5, with death occurring shortly after implantation and before gastrulation. Prmt1, however, was not detected in embryonic stem cell lines established from mutant blastocysts, suggesting it is not necessary for cell viability. Prmt1 -/- cells expressed approximately 8 times less methyltransferase activity than wildtype cells, indicating that the loss of Prmt1 activity is not compensated by an increase in other methyltransferases. In addition, high performance liquid chromatography (HPLC) and methyl acceptor activity analysis determined that the cell proteins of mutant cells were hypomethylated, whereas most potential substrates were already methylated in wildtype cells.
Abramovich, C., Yakobson, B., Chebath, J., Revel, M. A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor. EMBO J. 16: 260-266, 1997. [PubMed: 9029147] [Full Text: https://doi.org/10.1093/emboj/16.2.260]
An, W., Kim, J., Roeder, R. G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117: 735-748, 2004. [PubMed: 15186775] [Full Text: https://doi.org/10.1016/j.cell.2004.05.009]
Lin, W.-J., Gary, J. D., Yang, M. C., Clarke, S., Herschman, H. R. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J. Biol. Chem. 271: 15034-15044, 1996. [PubMed: 8663146] [Full Text: https://doi.org/10.1074/jbc.271.25.15034]
Mowen, K. A., Tang, J., Zhu, W., Schurter, B. T., Shuai, K., Herschman, H. R., David, M. Arginine methylation of STAT1 modulates IFN-alpha/beta-induce d transcription. Cell 104: 731-741, 2001. [PubMed: 11257227] [Full Text: https://doi.org/10.1016/s0092-8674(01)00269-0]
Nikawa, J., Nakano, H., Ohi, N. Structural and functional conservation of human and yeast HCP1 genes which can suppress the growth defect of the Saccharomyces cerevisiae ire15 mutant. Gene 171: 107-111, 1996. [PubMed: 8675017] [Full Text: https://doi.org/10.1016/0378-1119(96)00073-x]
Pawlak, M. R., Scherer, C. A., Chen, J., Roshon, M. J., Ruley, H. E. Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable. Molec. Cell. Biol. 20: 4859-4869, 2000. [PubMed: 10848611] [Full Text: https://doi.org/10.1128/MCB.20.13.4859-4869.2000]
Scorilas, A., Black, M. H., Talieri, M., Diamandis, E. P. Genomic organization, physical mapping, and expression analysis of the human protein arginine methyltransferase 1 gene. Biochem. Biophys. Res. Commun. 278: 349-359, 2000. [PubMed: 11097842] [Full Text: https://doi.org/10.1006/bbrc.2000.3807]
Scott, H. S., Antonarakis, S. E., Lalioti, M. D., Rossier, C., Silver, P. A., Henry, M. F. Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2). Genomics 48: 330-340, 1998. [PubMed: 9545638] [Full Text: https://doi.org/10.1006/geno.1997.5190]
Wang, H., Huang, Z.-Q., Xia, L., Feng, Q., Erdjument-Bromage, H., Strahl, B. D., Briggs, S. D., Allis, C. D., Wong, J., Tempst, P., Zhang, Y. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293: 853-857, 2001. [PubMed: 11387442] [Full Text: https://doi.org/10.1126/science.1060781]
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]