Brr2 is a splicing fidelity factor

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Abstract Many spliceosomal DExD/H box helicases act as fidelity factors during pre-mRNA splicing, promoting on-pathway interactions while simultaneously minimizing errors. Mutations linked to Retinitis Pigmentosa (RP), a form of heritable blindness, map to key domains of spliceosomal helicase Brr2 ( SNRNP200 in humans). Previous data show that such mutations negatively impact spliceosome activation, likely due to defects in brr2-RP RNA binding, helicase, and ATPase activities. Furthermore, data from human reporter constructs suggest that brr2-RP might impact 5′ splice site selection. Here we undertake a systematic analysis of brr2-RP effects on splicing fidelity. We show that a subset of brr2-RP mutants exhibit intron retention in vivo . Furthermore, brr2-RP mutants display hyperaccurate and/or error-prone splicing of a variety of splicing reporters. Branch-site fidelity is particularly impacted in this reporter assay. In addition, multiple brr2-RP alleles genetically interact with prp16 alleles known to impact the fidelity of branch site selection. Together these data implicate Brr2 in the fidelity of branch-site selection, and suggest that RP results not just from defects in spliceosome activation, but also from fidelity defects arising throughout the splicing cycle and in splicing fidelity.

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