Disease relevance of PRMT5

• Recombinant glutathione S-transferase-PRMT5 protein expressed in Escherichia coli also contained the catalytic activity [1].
• We found that JBP1, known as a human homolog (Skb1Hs) of Skb1 of fission yeast, interacts with NS3 of the hepatitis C virus in a yeast two-hybrid screen [1].
• We show that two main components of the SMN/PRMT5 system, namely the survival motor neuron (SMN) protein (reduced levels thereof causing spinal muscular atrophy) and pICln, are phosphorylated in vivo [2].
• Western blotting and immunohistochemical analyses for CDC20 and SKB1 showed overexpression and localization changes of the corresponding protein in human gastric cancer tissues [3].

High impact information on PRMT5

• We have now identified a homolog of JBP1, JBP2, containing a domain related to the SWI2/SNF2 family of chromatin remodeling proteins that is upregulated in bloodstream form cells and interacts with nuclear chromatin [4].
• We have previously identified a J binding protein (JBP1) involved in propagating J synthesis [4].
• The PRMT5 complex, previously implicated in methylation and storage of Sm proteins, interacts with the SMN complex and enhances its activity in an ATP-dependent manner [5].
• These phenotypes suggest a possible role for Skb1 as a mitotic inhibitor [6].
• Homologs of Skb1 are encoded by open reading frames in the genomes of S. cerevisiae and Caenorhabditis elegans and by an uncharacterized human cDNA sequence [7].

Biological context of PRMT5

• Its pICln subunit binds Sm proteins whereas the PRMT5 subunit catalyzes the methylation reaction [8].
• Amino acid sequence analysis revealed that Skb1Hs/JBP1 contains conserved motifs of S-adenosyl-l-methionine-dependent protein-arginine methyltransferases (PRMTs) [1].
• These findings suggest that the BRG1- and hBRM-associated PRMT5 regulates cell growth and proliferation by controlling expression of genes involved in tumor suppression [9].
• Chromatin immunoprecipitation experiments revealed that PRMT5 and MBD2 are recruited to CpG islands in a methylation-dependent manner in vivo and that H4R3, a substrate of PRMT, is methylated at these loci [10].
• Two of these proteins, termed RmtA (arginine methyltransferase A) and RmtC, reveal significant sequence homology to the well-characterized human proteins PRMT1 and PRMT5, respectively [11].

Anatomical context of PRMT5

• To elucidate the role played by PRMT5 in gene regulation, we have established a PRMT5 antisense cell line and determined by microarray analysis that more genes are derepressed when PRMT5 levels are reduced [9].
• A mutation introduced into the S-adenosyl-l-methionine-binding motif I of a myc-tagged PRMT5 construct in COS-1 cells led to a near complete loss of observed enzymatic activity [12].
• A hemagglutinin peptide-tagged PRMT5 complex purified from human HeLa cells catalyzes the S-adenosyl-l-[methyl-(3)H]methionine-dependent in vitro methylation of myelin basic protein [12].
• Human PRMT5 expression is enhanced during in vitro tubule formation and after in vivo ischemic injury in renal epithelial cells [13].
• We also demonstrated that expression of PRMT5 is enhanced in the renal tubular epithelium of animals subjected to ischemic reperfusion injury (IRI) [13].

Associations of PRMT5 with chemical compounds

• Myelin basic protein methylated by PRMT5 contained monomethylated and dimethylated arginine residues [1].
• Sedimentation analysis of purified PRMT5 on a sucrose density gradient indicated that PRMT5 formed distinct homo-oligomeric complexes, including a dimer and tetramer, that comigrated with the enzyme activity [1].
• In experiments with Leishmania tarentolae set up to disrupt the gene encoding the J-binding protein 1 (JBP1), a protein binding to the unusual base beta-D-glucosyl-hydroxymethyluracil (J) of Leishmania, we obtained JBP1 mutants containing linear DNA elements (amplicons) of approximately 100 kb [14].

Physical interactions of PRMT5

• This implies that the PRMT5 complex is involved in an early stage of U7 snRNP assembly and hence may have a second snRNP assembly function unrelated to sDMA modification [8].
• Protein-protein interaction studies indicate that PRMT5 and mSin3A interact with the same hSWI/SNF subunits as those targeted by c-Myc [15].
• We show that MEP50 is important for methylosome activity and binds to JBP1 and to a subset of Sm proteins [16].
• Markedly, recombinant COPR5 binds to the amino terminus of histone H4 and is required to recruit PRMT5 to reconstituted nucleosomes in vitro [17].

Other interactions of PRMT5

• PRMT5 appears to have lower specific enzyme activity than PRMT1 [1].
• The data demonstrate that PRMT7 (like PRMT5) is a Type II methyltransferase capable of producing SDMA modifications in proteins [18].
• Intriguingly, both the PRMT5 and ERH proteins are interacting partners of the SPT5 elongation factor [19].
• In this study, we assessed the impact of DAL-1/4.1B binding on the activity of another family member, PRMT5, both in vitro and in cells [20].
• Using chromatin immunoprecipitation assays, we found that Brg1, mSin3A, HDAC2, and PRMT5 are directly recruited to the cad promoter [15].

Analytical, diagnostic and therapeutic context of PRMT5

• Western blot analysis of sedimentation fractions suggests that endogenous PRMT5 is present as a homo-oligomer in a 293T cell extract [1].
• Interaction between PRMT5 and FCP1 was further confirmed by co-immunoprecipitation of endogenous proteins [19].

References