Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point
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 selecti...
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Elsevier
2015-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715010785 |
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doaj-ff6c0ceb5e1f4d5b93d3d3ccbbf6a31c2020-11-24T21:27:49ZengElsevierCell Reports2211-12472015-11-011351033104510.1016/j.celrep.2015.09.053Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch PointRachel B. Darman0Michael Seiler1Anant A. Agrawal2Kian H. Lim3Shouyong Peng4Daniel Aird5Suzanna L. Bailey6Erica B. Bhavsar7Betty Chan8Simona Colla9Laura Corson10Jacob Feala11Peter Fekkes12Kana Ichikawa13Gregg F. Keaney14Linda Lee15Pavan Kumar16Kaiko Kunii17Crystal MacKenzie18Mark Matijevic19Yoshiharu Mizui20Khin Myint21Eun Sun Park22Xiaoling Puyang23Anand Selvaraj24Michael P. Thomas25Jennifer Tsai26John Y. Wang27Markus Warmuth28Hui Yang29Ping Zhu30Guillermo Garcia-Manero31Richard R. Furman32Lihua Yu33Peter G. Smith34Silvia Buonamici35H3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USADepartment of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USADepartment of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAEisai, Inc., Andover, MA 01810, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAEisai, Inc., Andover, MA 01810, USAEisai, Inc., Andover, MA 01810, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAEisai, Inc., Andover, MA 01810, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USADepartment of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USADepartment of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USAH3 Biomedicine, Inc., Cambridge, MA 02139, USARecurrent 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.http://www.sciencedirect.com/science/article/pii/S2211124715010785 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Rachel B. Darman Michael Seiler Anant A. Agrawal Kian H. Lim Shouyong Peng Daniel Aird Suzanna L. Bailey Erica B. Bhavsar Betty Chan Simona Colla Laura Corson Jacob Feala Peter Fekkes Kana Ichikawa Gregg F. Keaney Linda Lee Pavan Kumar Kaiko Kunii Crystal MacKenzie Mark Matijevic Yoshiharu Mizui Khin Myint Eun Sun Park Xiaoling Puyang Anand Selvaraj Michael P. Thomas Jennifer Tsai John Y. Wang Markus Warmuth Hui Yang Ping Zhu Guillermo Garcia-Manero Richard R. Furman Lihua Yu Peter G. Smith Silvia Buonamici |
| spellingShingle |
Rachel B. Darman Michael Seiler Anant A. Agrawal Kian H. Lim Shouyong Peng Daniel Aird Suzanna L. Bailey Erica B. Bhavsar Betty Chan Simona Colla Laura Corson Jacob Feala Peter Fekkes Kana Ichikawa Gregg F. Keaney Linda Lee Pavan Kumar Kaiko Kunii Crystal MacKenzie Mark Matijevic Yoshiharu Mizui Khin Myint Eun Sun Park Xiaoling Puyang Anand Selvaraj Michael P. Thomas Jennifer Tsai John Y. Wang Markus Warmuth Hui Yang Ping Zhu Guillermo Garcia-Manero Richard R. Furman Lihua Yu Peter G. Smith Silvia Buonamici Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point Cell Reports |
| author_facet |
Rachel B. Darman Michael Seiler Anant A. Agrawal Kian H. Lim Shouyong Peng Daniel Aird Suzanna L. Bailey Erica B. Bhavsar Betty Chan Simona Colla Laura Corson Jacob Feala Peter Fekkes Kana Ichikawa Gregg F. Keaney Linda Lee Pavan Kumar Kaiko Kunii Crystal MacKenzie Mark Matijevic Yoshiharu Mizui Khin Myint Eun Sun Park Xiaoling Puyang Anand Selvaraj Michael P. Thomas Jennifer Tsai John Y. Wang Markus Warmuth Hui Yang Ping Zhu Guillermo Garcia-Manero Richard R. Furman Lihua Yu Peter G. Smith Silvia Buonamici |
| author_sort |
Rachel B. Darman |
| title |
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point |
| title_short |
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point |
| title_full |
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point |
| title_fullStr |
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point |
| title_full_unstemmed |
Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3′ Splice Site Selection through Use of a Different Branch Point |
| title_sort |
cancer-associated sf3b1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2015-11-01 |
| description |
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. |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124715010785 |
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