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

被引：375

作者：

Darman, Rachel B. ^{[1
]}

Seiler, Michael ^{[1
]}

Agrawal, Anant A. ^{[1
]}

Lim, Kian H. ^{[1
]}

Peng, Shouyong ^{[1
]}

Aird, Daniel ^{[1
]}

Bailey, Suzanna L. ^{[1
]}

Bhavsar, Erica B. ^{[2
]}

Chan, Betty ^{[1
]}

Colla, Simona ^{[3
]}

Corson, Laura ^{[1
]}

Feala, Jacob ^{[1
]}

Fekkes, Peter ^{[1
]}

Ichikawa, Kana ^{[1
]}

Keaney, Gregg F. ^{[1
]}

Lee, Linda ^{[1
]}

Kumar, Pavan ^{[4
]}

Kunii, Kaiko ^{[1
]}

MacKenzie, Crystal ^{[4
]}

Matijevic, Mark ^{[4
]}

Mizui, Yoshiharu ^{[1
]}

Myint, Khin ^{[4
]}

Park, Eun Sun ^{[1
]}

Puyang, Xiaoling ^{[1
]}

Selvaraj, Anand ^{[1
]}

Thomas, Michael P. ^{[1
]}

Tsai, Jennifer ^{[1
]}

Wang, John Y. ^{[1
]}

Warmuth, Markus ^{[1
]}

Yang, Hui ^{[3
]}

Zhu, Ping ^{[1
]}

Garcia-Manero, Guillermo ^{[3
]}

Furman, Richard R. ^{[2
]}

Yu, Lihua ^{[1
]}

Smith, Peter G. ^{[1
]}

Buonamici, Silvia ^{[1
]}

机构：

[1] H3 Biomed Inc, Cambridge, MA 02139 USA

[2] Weill Cornell Med Coll, Dept Hematol Oncol, New York, NY 10020 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[4] Eisai Inc, Andover, MA 01810 USA

来源：

CELL REPORTS | 2015年 / 13卷 / 05期

基金：

美国国家卫生研究院;

关键词：

RING SIDEROBLASTS; UVEAL MELANOMA; FACTOR HSLU7; RNA; RECOGNITION; EXPRESSION; GENES; MYELODYSPLASIA; MALIGNANCIES; STEP;

D O I：

10.1016/j.celrep.2015.09.053

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 30 splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 30 ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wildtype SF3B1 and requires the canonical 30 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.

引用

页码：1033 / 1045

页数：13

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