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MBC in Press, published online ahead of print July 19, 2006
Mol. Biol. Cell 10.1091/mbc.E06-01-0036

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Submitted on January 13, 2006
Revised on July 10, 2006
Accepted on July 11, 2006

RNAi Knockdown of hU2AF35 Impairs Cell Cycle Progression and Modulates Alternative Splicing of Cdc25 Transcripts

Teresa Raquel Pacheco,* Luís Ferreira Moita,*{dagger} Anita Quintal Gomes,*{ddagger} Nir Hacohen,{dagger} and Maria Carmo-Fonseca*

*Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; {dagger}Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129; {ddagger}Departamento de Ciências da Saúde, Universidade da Madeira, 9000-390 Funchal, Portugal

Monitoring Editor: Karsten Weis

U2AF is a heterodimeric splicing factor composed of a large (U2AF65) and a small (U2AF35) subunit. In humans, alternative splicing generates two U2AF35 variants, U2AF35a and U2AF35b. Here, we used RNA interference to specifically ablate the expression of each isoform in HeLa cells. Our results show that knockdown of the major U2AF35a isoform reduced cell viability and impaired mitotic progression leading to accumulation of cells in prometaphase. Microarray analysis revealed that knockdown of U2AF35a affected the expression level of ~500 mRNAs, from which >90% were underrepresented relative to the control. Among mRNAs under-represented in U2AF35a-depleted cells we identified an essential cell cycle gene, Cdc27, for which there was an increase in the ratio between unspliced and spliced RNA and a significant reduction in protein level. Furthermore, we show that depletion of either U2AF35a or U2AF35b altered the ratios of alternatively spliced isoforms of Cdc25B and Cdc25C transcripts. Taken together our results demonstrate that U2AF35a is essential for HeLa cell division and suggest a novel role for both U2AF35 protein isoforms as regulators of alternative splicing of a specific subset of genes.

Address correspondence to: Maria Carmo-Fonseca (carmo.fonseca{at}fm.ul.pt)




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