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Molecular and Cellular Biology, October 2008, p. 6262-6277, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00923-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Protein Arginine Methyltransferase 5 Suppresses the Transcription of the RB Family of Tumor Suppressors in Leukemia and Lymphoma Cells ^,

Li Wang, Sharmistha Pal, and Saïd Sif^*

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210

Received 9 June 2008/ Returned for modification 27 July 2008/ Accepted 30 July 2008

The proper epigenetic modification of chromatin by protein arginine methyltransferases (PRMTs) is crucial for normal cell growth and health. The human SWI/SNF-associated PRMT5 is involved in the transcriptional repression of target genes by directly methylating H3R8 and H4R3. To further understand the impact of PRMT5-mediated histone methylation on cancer, we analyzed its expression in normal and transformed human B lymphocytes. Our findings reveal that PRMT5 protein levels are enhanced in various human lymphoid cancer cells, including transformed chronic lymphocytic leukemia (B-CLL) cell lines. PRMT5 overexpression is caused by the altered expression of the PRMT5-specific microRNAs 19a, 25, 32, 92, 92b, and 96 and results in the increased global symmetric methylation of H3R8 and H4R3. An evaluation of both epigenetic marks at PRMT5 target genes such as RB1 (p105), RBL1 (p107), and RBL2 (p130) showed that promoters H3R8 and H4R3 are hypermethylated, which in turn triggers pocket protein transcriptional repression. Furthermore, reducing PRMT5 expression in WaC3CD5 B-CLL cells abolishes H3R8 and H4R3 hypermethylation, restores RBL2 expression, and inhibits cancer cell proliferation. These results indicate that PRMT5 overexpression epigenetically alters the transcription of key tumor suppressor genes and suggest a causal role of the elevated symmetric methylation of H3R8 and H4R3 at the RBL2 promoter in transformed B-lymphocyte pathology.

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* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, Ohio State University College of Medicine, Columbus, OH 43210. Phone: (614) 247-7445. Fax: (614) 292-4118. E-mail: sif.1{at}osu.edu

Published ahead of print on 11 August 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, October 2008, p. 6262-6277, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00923-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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