Oct 6, 2009

Engineering splicing factors with designed specificities

Nature Methods
Yang WangZefeng Wang

Abstract

Alternative splicing is generally regulated by trans-acting factors that specifically bind pre-mRNA to activate or inhibit the splicing reaction. This regulation is critical for normal gene expression, and dysregulation of splicing is closely associated with human diseases. Here we engineered artificial splicing factors by combining sequence-specific RNA-binding domains of human Pumilio1 with functional domains that regulate splicing. We applied these factors to modulate different types of alternative splicing in selected targets, to examine the activity of effector domains from natural splicing factors and to modulate splicing of an endogenous human gene, Bcl-X, an anticancer target. The designer factor targeted to Bcl-X increased the amount of pro-apoptotic Bcl-xS splice isoform, thus promoting apoptosis and increasing chemosensitivity of cancer cells to common antitumor drugs. Our approach permitted the creation of artificial factors to target virtually any pre-mRNA, providing a strategy to study splicing regulation and to manipulate disease-associated splicing events.

  • References31
  • Citations58

Mentioned in this Paper

Bcl-Xbeta Protein
Nested Transcripts
Antineoplastic Agents
Apoptosis, Intrinsic Pathway
Primary RNA Transcript
Bcl-x protein
BCL2L1 gene
Gene Expression
Human gene
Heterogeneous Nuclear RNA

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