Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer

Abstract

Genetic mutation, chromosomal rearrangement and copy number amplification are common mechanisms responsible for generating gain-of-function, cancer-causing alterations. Here we report a new mechanism by which premature cleavage and polyadenylation (pPA) of RNA can produce an oncogenic protein. We identify a pPA event at a cryptic intronic poly(A) signal in MAGI3, occurring in the absence of local exonic and intronic mutations. The altered mRNA isoform, called MAGI3pPA, produces a truncated protein that acts in a dominant-negative manner to prevent full-length MAGI3 from interacting with the YAP oncoprotein, thereby relieving YAP inhibition and promoting malignant transformation of human mammary epithelial cells. We additionally find evidence for recurrent expression of MAGI3pPA in primary human breast tumors but not in tumoradjacent normal tissues. Our results provide an example of how pPA contributes to cancer by generating a truncated mRNA isoform that encodes an oncogenic, gain-of-function protein.