SF2/ASF autoregulation involves multiple layers of post-transcriptional and translational control.
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.
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Shuying
S
Sun
Zuo
Z
Zhang
Rahul
R
Sinha
Rotem
R
Karni
Adrian R
AR
Krainer
D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D020871:RNA Stability / Q000235:genetics; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068103:Serine-Arginine Splicing Factors
D020413:3' Untranslated Regions; C000715470:MAS1 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors