| Literature DB >> 26565915 |
Rachel B Darman1, Michael Seiler1, Anant A Agrawal1, Kian H Lim1, Shouyong Peng1, Daniel Aird1, Suzanna L Bailey1, Erica B Bhavsar2, Betty Chan1, Simona Colla3, Laura Corson1, Jacob Feala1, Peter Fekkes1, Kana Ichikawa1, Gregg F Keaney1, Linda Lee1, Pavan Kumar4, Kaiko Kunii1, Crystal MacKenzie4, Mark Matijevic4, Yoshiharu Mizui1, Khin Myint4, Eun Sun Park1, Xiaoling Puyang1, Anand Selvaraj1, Michael P Thomas1, Jennifer Tsai1, John Y Wang1, Markus Warmuth1, Hui Yang3, Ping Zhu1, Guillermo Garcia-Manero3, Richard R Furman2, Lihua Yu1, Peter G Smith1, Silvia Buonamici5.
Abstract
Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3' splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3' ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3' ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.Entities:
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Year: 2015 PMID： 26565915 DOI： 10.1016/j.celrep.2015.09.053
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423