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Molecular and Cellular Biology, October 2008, p. 5924-5936, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00560-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Novel Splicing Factor RBM25 Modulates Bcl-x Pre-mRNA 5' Splice Site Selection

AnYu Zhou,^1,2 Alexander C. Ou,¹ Aeri Cho,¹ Edward J. Benz Jr.,^1,2,3,4,5 and Shu-Ching Huang^1,2*

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts,¹ Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts,² Dana-Farber/Harvard Cancer Center,³ Department of Pathology, Harvard Medical School, Boston, Massachusetts,⁴ Department of Pediatrics, Children's Hospital, Boston, Massachusetts⁵

Received 7 April 2008/ Returned for modification 6 May 2008/ Accepted 22 July 2008

RBM25 has been shown to associate with splicing cofactors SRm160/300 and assembled splicing complexes, but little is known about its splicing regulation. Here, we characterize the functional role of RBM25 in alternative pre-mRNA splicing. Increased RBM25 expression correlated with increased apoptosis and specifically affected the expression of Bcl-x isoforms. RBM25 stimulated proapoptotic Bcl-x_S 5' splice site (5' ss) selection in a dose-dependent manner, whereas its depletion caused the accumulation of antiapoptotic Bcl-x_L. Furthermore, RBM25 specifically bound to Bcl-x RNA through a CGGGCA sequence located within exon 2. Mutation in this element abolished the ability of RBM25 to enhance Bcl-x_S 5' ss selection, leading to decreased Bcl-x_S isoform expression. Binding of RBM25 was shown to promote the recruitment of the U1 small nuclear ribonucleoprotein particle (snRNP) to the weak 5' ss; however, it was not required when a strong consensus 5' ss was present. In support of a role for RBM25 in modulating the selection of a 5' ss, we demonstrated that RBM25 associated selectively with the human homolog of yeast U1 snRNP-associated factor hLuc7A. These data suggest a novel mode for Bcl-x_S 5' ss activation in which binding of RBM25 with exonic element CGGGCA may stabilize the pre-mRNA-U1 snRNP through interactions with hLuc7A.

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* Corresponding author. Mailing address: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-6965. Fax: (617) 632-2662. E-mail: shu-ching_huang{at}dfci.harvard.edu

Published ahead of print on 28 July 2008.

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Molecular and Cellular Biology, October 2008, p. 5924-5936, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00560-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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