title: 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 MAGI3(pPA), 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 MAGI3(pPA) in primary human breast tumors but not in tumor-adjacent 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.
authors.affiliation: Department of Developmental, Chemical and Molecular Biology, Tufts University, Boston, United States.|Molecular Oncology Research Institute, Boston, United States.|Tufts Medical Center, Boston, United States.
authors.forename: Thomas K
authors.identifier: 0000-0003-2961-0593
authors.initials: TK
authors.lastname: Ni
authors.affiliation: Department of Developmental, Chemical and Molecular Biology, Tufts University, Boston, United States.|Molecular Oncology Research Institute, Boston, United States.|Tufts Medical Center, Boston, United States.
authors.forename: Charlotte
authors.identifier: 0000-0001-7913-9619
authors.initials: C
authors.lastname: Kuperwasser
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D050505:Mutant Proteins / Q000096:biosynthesis* / Q000235:genetics; D026723:Polyadenylation; D059368:RNA Isoforms / Q000235:genetics / Q000378:metabolism*
chemical_list: C496469:MAGI3 protein, human; D008565:Membrane Proteins; D050505:Mutant Proteins; D059368:RNA Isoforms
keywords: Hippo pathway; MAGI3; YAP; breast cancer; chromosomes; cleavage and polyadenylation; cryptic poly(A) signal; genes; human; human biology; medicine; mouse