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Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point.
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.
Affiliation
  • Darman RB; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Seiler M; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Agrawal AA; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Lim KH; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Peng S; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Aird D; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Bailey SL; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Bhavsar EB; Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
  • Chan B; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Colla S; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Corson L; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Feala J; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Fekkes P; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Ichikawa K; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Keaney GF; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Lee L; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Kumar P; Eisai, Inc., Andover, MA 01810, USA.
  • Kunii K; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • MacKenzie C; Eisai, Inc., Andover, MA 01810, USA.
  • Matijevic M; Eisai, Inc., Andover, MA 01810, USA.
  • Mizui Y; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Myint K; Eisai, Inc., Andover, MA 01810, USA.
  • Park ES; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Puyang X; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Selvaraj A; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Thomas MP; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Tsai J; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Wang JY; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Warmuth M; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Yang H; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhu P; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Garcia-Manero G; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Furman RR; Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
  • Yu L; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Smith PG; H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
  • Buonamici S; H3 Biomedicine, Inc., Cambridge, MA 02139, USA. Electronic address: silvia_buonamici@h3biomedicine.com.
Cell Rep ; 13(5): 1033-45, 2015 Nov 03.
Article in En | MEDLINE | ID: mdl-26565915
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.
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Full text: 1 Database: MEDLINE Main subject: Phosphoproteins / Ribonucleoprotein, U2 Small Nuclear / Alternative Splicing / Mutation / Neoplasms Type of study: Risk_factors_studies Limits: Humans Language: En Year: 2015 Type: Article
Fulltext
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Full text: 1 Database: MEDLINE Main subject: Phosphoproteins / Ribonucleoprotein, U2 Small Nuclear / Alternative Splicing / Mutation / Neoplasms Type of study: Risk_factors_studies Limits: Humans Language: En Year: 2015 Type: Article