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2018 ; 46
(5
): 2145-2158
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The mechanisms of a mammalian splicing enhancer
#MMPMID29394380
Jobbins AM
; Reichenbach LF
; Lucas CM
; Hudson AJ
; Burley GA
; Eperon IC
Nucleic Acids Res
2018[Mar]; 46
(5
): 2145-2158
PMID29394380
show ga
Exonic splicing enhancer (ESE) sequences are bound by serine & arginine-rich (SR)
proteins, which in turn enhance the recruitment of splicing factors. It was
inferred from measurements of splicing around twenty years ago that Drosophila
doublesex ESEs are bound stably by SR proteins, and that the bound proteins
interact directly but with low probability with their targets. However, it has
not been possible with conventional methods to demonstrate whether mammalian ESEs
behave likewise. Using single molecule multi-colour colocalization methods to
study SRSF1-dependent ESEs, we have found that that the proportion of RNA
molecules bound by SRSF1 increases with the number of ESE repeats, but only a
single molecule of SRSF1 is bound. We conclude that initial interactions between
SRSF1 and an ESE are weak and transient, and that these limit the activity of a
mammalian ESE. We tested whether the activation step involves the propagation of
proteins along the RNA or direct interactions with 3' splice site components by
inserting hexaethylene glycol or abasic RNA between the ESE and the target 3'
splice site. These insertions did not block activation, and we conclude that the
activation step involves direct interactions. These results support a model in
which regulatory proteins bind transiently and in dynamic competition, with the
result that each ESE in an exon contributes independently to the probability that
an activator protein is bound and in close proximity to a splice site.
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