Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point.
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 Information
Rachel B Darman: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Michael Seiler: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Anant A Agrawal: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Kian H Lim: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Shouyong Peng: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Daniel Aird: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Suzanna L Bailey: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Erica B Bhavsar: Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
Betty Chan: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Simona Colla: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Laura Corson: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Jacob Feala: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Peter Fekkes: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Kana Ichikawa: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Gregg F Keaney: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Linda Lee: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Pavan Kumar: Eisai, Inc., Andover, MA 01810, USA.
Kaiko Kunii: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Crystal MacKenzie: Eisai, Inc., Andover, MA 01810, USA.
Mark Matijevic: Eisai, Inc., Andover, MA 01810, USA.
Yoshiharu Mizui: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Khin Myint: Eisai, Inc., Andover, MA 01810, USA.
Eun Sun Park: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Xiaoling Puyang: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Anand Selvaraj: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Michael P Thomas: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Jennifer Tsai: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
John Y Wang: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Markus Warmuth: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Hui Yang: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ping Zhu: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Guillermo Garcia-Manero: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Richard R Furman: Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
Lihua Yu: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Peter G Smith: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
Silvia Buonamici: H3 Biomedicine, Inc., Cambridge, MA 02139, USA. Electronic address: silvia_buonamici@h3biomedicine.com.
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.
