Negative regulation of transcription by the type II arginine methyltransferase PRMT5

We have identified previously a repressor element in the transcription start site region of the cyclin E1 promoter that periodically associates with an atypical, high molecular weight E2F complex, termed CERC. Purification of native CERC reveals the presence of the type II arginine methyltransferase PRMT5, which can mono‐ or symetrically dimethylate arginine residues in proteins. Chromatin immunoprecipitations (ChIPs) show that PRMT5 is associated specifically with the transcription start site region of the cyclin E1 promoter. ChIP analyses also show that this correlates with the presence on the same promoter region of arginine‐methylated proteins including histone H4, an in vitro substrate of PRMT5. Consistent with its presence within the repressor complex, forced expression of PRMT5 negatively affects cyclin E1 promoter activity and cellular proliferation, effects that require its methyltransferase activity. These data provide the first direct experimental evidence that a type II arginine methylase is involved in the control of transcription and proliferation.

[1]  D. Reinberg,et al.  Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. , 2001, Genes & development.

[2]  Tony Kouzarides,et al.  Retinoblastoma protein recruits histone deacetylase to repress transcription , 1998, Nature.

[3]  Duanduan Ma,et al.  Exit from G1 and S Phase of the Cell Cycle Is Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF , 2000, Cell.

[4]  C. Sardet,et al.  Timing of cyclin E gene expression depends on the regulated association of a bipartite repressor element with a novel E2F complex , 1999, The EMBO journal.

[5]  M. Grunstein,et al.  A search for proteins that interact genetically with histone H3 and H4 amino termini uncovers novel regulators of the Swe1 kinase in Saccharomyces cerevisiae. , 1996, Genes & development.

[6]  R. Weinberg,et al.  Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. , 1996, Oncogene.

[7]  Andrew J. Bannister,et al.  Rb targets histone H3 methylation and HP1 to promoters , 2001, Nature.

[8]  C. Allis,et al.  Hormone-dependent, CARM1-directed, arginine-specific methylation of histone H3 on a steroid-regulated promoter , 2001, Current Biology.

[9]  Marc Montminy,et al.  A Transcriptional Switch Mediated by Cofactor Methylation , 2001, Science.

[10]  T. Kouzarides,et al.  Methylation at arginine 17 of histone H3 is linked to gene activation , 2002, EMBO reports.

[11]  C. Sardet,et al.  Retinoblastoma Protein Transcriptional Repression through Histone Deacetylation of a Single Nucleosome , 2002, Molecular and Cellular Biology.

[12]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[13]  D. Aswad,et al.  Regulation of transcription by a protein methyltransferase. , 1999, Science.

[14]  S. Clarke,et al.  RNA and protein interactions modulated by protein arginine methylation. , 1998, Progress in nucleic acid research and molecular biology.

[15]  C. Sardet,et al.  The periodic down regulation of Cyclin E gene expression from exit of mitosis to end of G1 is controlled by a deacetylase- and E2F-associated bipartite repressor element , 2001, Oncogene.

[16]  Juri Rappsilber,et al.  The Methylosome, a 20S Complex Containing JBP1 and pICln, Produces Dimethylarginine-Modified Sm Proteins , 2001, Molecular and Cellular Biology.

[17]  Wei Zhu,et al.  Arginine Methylation of STAT1 Modulates IFNα/β-Induced Transcription , 2001, Cell.

[18]  M. Vidal,et al.  E2Fs and the Retinoblastoma Protein Family , 1997 .

[19]  M. Yaniv,et al.  Oncogenes as Transcriptional Regulators , 1997, Progress in Gene Expression.

[20]  Steven Clarke,et al.  PRMT5 (Janus Kinase-binding Protein 1) Catalyzes the Formation of Symmetric Dimethylarginine Residues in Proteins* , 2001, The Journal of Biological Chemistry.

[21]  R. Medema,et al.  Cyclin A Is a Mediator of p120E4F-Dependent Cell Cycle Arrest in G1 , 2001, Molecular and Cellular Biology.

[22]  C. Allis,et al.  Methylation of Histone H4 at Arginine 3 Facilitating Transcriptional Activation by Nuclear Hormone Receptor , 2001, Science.

[23]  R. Medema,et al.  Cyclin A Is a Mediator of p 120 E 4 F-Dependent Cell Cycle Arrest in G 1 , 2001 .

[24]  Brian D. Strahl,et al.  Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1 , 2001, Current Biology.

[25]  P. Becker,et al.  The histone H4 acetyltransferase MOF uses a C2HC zinc finger for substrate recognition , 2001, EMBO reports.

[26]  S. Pestka,et al.  The Human Homologue of the Yeast Proteins Skb1 and Hsl7p Interacts with Jak Kinases and Contains Protein Methyltransferase Activity* , 1999, The Journal of Biological Chemistry.

[27]  G. Bartholomeusz,et al.  Negative regulation of mitosis in fission yeast by the shk1 interacting protein skb1 and its human homolog, Skb1Hs. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  F. Inose,et al.  Hsl7p, a negative regulator of Ste20p protein kinase in the Saccharomyces cerevisiae filamentous growth-signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.