Repression of prespliceosome complex formation at two distinct steps by fox-1/fox-2 proteins

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Courtesy of American Society for Microbiology

Precise and robust regulation of alternative splicing provides cells with an essential means of gene expression control. However, the mechanisms that ensure the tight control of tissue-specific alternative splicing are not well understood. It has been demonstrated that robust regulation often results from the contributions of multiple factors to one particular splicing pathway. We report here a novel strategy used by a single splicing regulator that blocks the formation of two distinct prespliceosome complexes to achieve efficient regulation. Fox-1/Fox-2 proteins, potent regulators of alternative splicing in the heart, skeletal muscle, and brain, repress calcitonin-specific splicing of the calcitonin/CGRP pre-mRNA. Using biochemical analysis, we found that Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. First, Fox-1/Fox-2 proteins bind to the intronic site to inhibit SF1-dependent E' complex formation. Second, these proteins bind to the exonic site to block the transition of E' complex that escaped the control of the intronic site to E complex. These studies provide evidence for the first example of regulated E' complex formation. The two-step repression of presplicing complexes by a single regulator provides a powerful and accurate regulatory strategy.

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