Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point

• Published in: Cell reports (Cambridge) Vol. 13; no. 5; pp. 1033 - 1045
• Main Authors: Darman, Rachel B., Seiler, Michael, Agrawal, Anant A., Lim, Kian H., Peng, Shouyong, Aird, Daniel, Bailey, Suzanna L., Bhavsar, Erica B., Chan, Betty, Colla, Simona, Corson, Laura, Feala, Jacob, Fekkes, Peter, Ichikawa, Kana, Keaney, Gregg F., Lee, Linda, Kumar, Pavan, Kunii, Kaiko, MacKenzie, Crystal, Matijevic, Mark, Mizui, Yoshiharu, Myint, Khin, Park, Eun Sun, Puyang, Xiaoling, Selvaraj, Anand, Thomas, Michael P., Tsai, Jennifer, Wang, John Y., Warmuth, Markus, Yang, Hui, Zhu, Ping, Garcia-Manero, Guillermo, Furman, Richard R., Yu, Lihua, Smith, Peter G., Buonamici, Silvia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2015; Elsevier
• Subjects: Alleles; Alternative Splicing; Amino Acid Sequence; Base Sequence; HEK293 Cells; Humans; Molecular Sequence Data; Mutation; Mutation Rate; Neoplasms - genetics; Nonsense Mediated mRNA Decay; Phosphoproteins - chemistry; Phosphoproteins - genetics; Phosphoproteins - metabolism; Ribonucleoprotein, U2 Small Nuclear - chemistry; Ribonucleoprotein, U2 Small Nuclear - genetics; Ribonucleoprotein, U2 Small Nuclear - metabolism; RNA Splicing Factors
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.09.053

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. [Display omitted] •SF3B1 hotspot mutations are neomorphic and induce aberrant 3′ splice site selection•Mutant SF3B1 utilizes a different branch point than that used by wild-type SF3B1•SF3B1 mutants require the canonical 3′ splice site to induce aberrant splicing•∼50% of aberrant mRNAs undergo NMD leading to downregulation of canonical isoforms Darman et al. report that SF3B1 mutations found in cancer induce aberrant 3′ splice site selection. To induce aberrant splicing, mutant SF3B1 requires canonical 3′ splice site but utilizes a different branch point than wild-type SF3B1. Approximately 50% of the aberrant mRNAs undergo NMD resulting in downregulation of canonical transcripts.