SF2/ASF is a prototypical serine-and arginine-rich protein, with important roles in splicing and other aspects of mRNA metabolism. Splicing factor, arginine/serine-rich 1 (SFRS1), the gene encoding SF2/ASF, is a potent proto-oncogene with abnormal expression in many tumors. We found that SF2/ASF negatively autoregulates its expression to maintain homeostatic levels. We characterized six alternatively spliced SF2/ASF mRNA isoforms: the major isoform encodes full-length protein, whereas the others are either retained in the nucleus or degraded by nonsense-mediated mRNA decay. Unproductive splicing accounts for only part of the autoregulation, which occurs primarily at the translational level. The effect is specific to SF2/ASF and requires RNA recognition motif 2 (RRM2). The ultraconserved 3′ untranslated region (UTR) is necessary and sufficient for downregulation. SF2/ASF overexpression shifts the distribution of target mRNA toward monoribosomes, and translational repression is partly independent of Dicer and a 5′ cap. Thus, multiple post-transcriptional and translational mechanisms are involved in fine-tuning the expression of SF2/ASF.
Bibliographical noteFunding Information:
We thank B. Vogelstein (Johns Hopkins University) for generously providing the DicerEx5/Ex5 RKO cell line, G. Hannon (Cold Spring Harbor Laboratory) for sharing the Dicer−/− and Dicer+/− ES cells, V. Racaniello (Columbia University) for the gift of HCV and CrPV IRES plasmids, C. Xue for statistical analysis, Y. Yu for advice on polysome gradients and J. Zhu for helpful discussions and communicating unpublished results. This work was supported by US National Cancer Institute grant CA13106.