Prp8 impacts cryptic but not alternative splicing frequency

Significance The spliceosome selects, and in the case of alternative splicing, contextually distinguishes between, splice sites with extremely high fidelity. However, when a splice site becomes mutated, as in many human diseases, the spliceosome can aberrantly select nearby “cryptic” splice sites, which produce nonfunctional protein. It is unclear how the spliceosome routinely selects against cryptic sequences. Here, we implicate core components of the spliceosome itself in its ability to select against cryptic splice sites and show that how the spliceosome selects against cryptic splice sites is different than how it selects between bona fide splice sites during alternative splicing. In addition to providing insight into an essential cellular process, our work is relevant to the development of therapeutics that act by modulating splice-site choice.