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Journal of Virology, October 2009, p. 9844-9853, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01014-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Growth-Promoting Properties of Epstein-Barr Virus EBER-1 RNA Correlate with Ribosomal Protein L22 Binding{triangledown}

Jennifer L. Houmani,{dagger} Christopher I. Davis, and Ingrid K. Ruf*

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900

Received 19 May 2009/ Accepted 16 July 2009

The Epstein-Barr virus (EBV)-encoded RNAs, EBER-1 and EBER-2, are highly abundant noncoding nuclear RNAs expressed during all forms of EBV latency. The EBERs have been shown to impart significant tumorigenic potential upon EBV-negative Burkitt lymphoma (BL) cells and to contribute to the growth potential of other B-cell lymphoma-, gastric carcinoma-, and nasopharyngeal carcinoma-derived cell lines. However, the mechanisms underlying this EBER-dependent enhancement of cell growth potential remain to be elucidated. Here we focused on the known interaction between EBER-1 and the cellular ribosomal protein L22 and the consequences of this interaction with respect to the growth-promoting properties of the EBERs. L22, a component of 60S ribosomal subunits, binds three sites on EBER-1, and a substantial fraction of available L22 is relocalized from nucleoli to the nucleoplasm in EBV-infected cells. To investigate the hypothesis that EBER-1-mediated relocalization of L22 in EBV-infected cells is critical for EBER-dependent functions, we investigated whether EBER-1 expression is necessary and sufficient for nucleoplasmic retention of L22. Following demonstration of this, we utilized RNA-protein binding assays and fluorescence localization studies to demonstrate that mutation of the L22 binding sites on EBER-1 prevents L22 binding and inhibits EBER-1-dependent L22 relocalization. Finally, the in vivo consequence of preventing L22 relocalization in EBER-expressing cells was examined in soft agar colony formation assays. We demonstrate that BL cells expressing mutated EBER-1 RNAs rendered incapable of binding L22 have significantly reduced capacity to enhance cell growth potential relative to BL cells expressing wild-type EBERs.

* Corresponding author. Mailing address: Department of Molecular Biology and Biochemistry, University of California, Irvine, 3236 McGaugh Hall, Irvine, CA 92697-3900. Phone: (949) 824-4485. Fax: (949) 824-8551. E-mail: iruf{at}uci.edu

{triangledown} Published ahead of print on 29 July 2009.

{dagger} Present address: Shriner's Hospital for Children, Research Division, Portland, OR 97239.

Journal of Virology, October 2009, p. 9844-9853, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01014-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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