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J. Biol. Chem., Vol. 281, Issue 49, 37381-37390, December 8, 2006

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Murine Leukemia Virus Regulates Alternative Splicing through Sequences Upstream of the 5· Splice Site^*

Janine Kraunus^¶, Daniela Zychlinski, Tilman Heise, Melanie Galla, Jens Bohne¹, and Christopher Baum^||2

From the Department of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany, the Department of General Virology, Heinrich-Pette-Institute D-20251 Hamburg, Germany, the ^¶Bone Marrow Transplantation, University Hospital Eppendorf, D-20246 Hamburg, Germany, and the ^||Division of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, Ohio 45229

Alternative splicing of the primary transcript plays a key role in retroviral gene expression. In contrast to all known mechanisms that mediate alternative splicing in retroviruses, we found that in murine leukemia virus, distinct elements located upstream of the 5' splice site either inhibited or activated splicing of the genomic RNA. Detailed analysis of the first untranslated exon showed that the primer binding site (PBS) activates splicing, whereas flanking sequences either downstream or upstream of the PBS are inhibitory. This new function of the PBS was independent of its orientation and primer binding but associated with a particular destabilizing role in a proposed secondary structure. On the contrary, all sequences surrounding the PBS that are involved in stem formation of the first exon were found to suppress splicing. Targeted mutations that destabilized the central stem and compensatory mutations of the counter strand clearly validated the concept that murine leukemia virus attenuates its 5' splice site by forming an inhibitory stem-loop in its first exon. Importantly, this mode of splice regulation was conserved in a complete proviral clone. Some of the mutants that increase splicing revealed an opposite effect on translation, implying that the first exon also regulates this process. Together, these findings suggest that sequences upstream of the 5' splice site play an important role in splice regulation of simple retroviruses, directly or indirectly attenuating the efficiency of splicing.

Received for publication, February 17, 2006 , and in revised form, October 10, 2006.

^* The work was supported by Deutsche Forschungsgemeinschaft Grant 1837/Ba4 and the European Union (INHERINET and CONSERT grants). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ To whom correspondence may be addressed: Dept. of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-532-6067; Fax: 49-511-532-6068; E-mail: bohne.jens{at}mh-hannover.de. ² To whom correspondence may be addressed: Dept. of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-532-6067; Fax: 49-511-532-6068; E-mail: baum.christopher{at}mh-hannover.de.

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