RT Journal Article
SR Electronic
T1 Wild-type U2AF1 antagonizes the splicing program characteristic of U2AF1-mutant tumors and is required for cell survival
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 048553
DO 10.1101/048553
A1 Dennis Liang Fei
A1 Hayley Motowski
A1 Rakesh Chatrikhi
A1 Sameer Prasad
A1 Jovian Yu
A1 Shaojian Gao
A1 Clara L. Kielkopf
A1 Robert K. Bradley
A1 Harold Varmus
YR 2016
UL http://biorxiv.org/content/early/2016/05/20/048553.abstract
AB We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3' splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3' splice sites. Finally, we show that lung adenocarcinoma cell lines are independent on mutant U2AF1 for growth in vitro or in vivo. In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide a mechanistic explanation of the magnitude of splicing changes observed in U2AF1-mutant cells, and explain why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele.