title: Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point.
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.
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Darman
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Seiler
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Anant A
authors.initials: AA
authors.lastname: Agrawal
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Kian H
authors.initials: KH
authors.lastname: Lim
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aird
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Suzanna L
authors.initials: SL
authors.lastname: Bailey
authors.affiliation: Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
authors.forename: Erica B
authors.initials: EB
authors.lastname: Bhavsar
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Chan
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Feala
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Fekkes
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Kana
authors.initials: K
authors.lastname: Ichikawa
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Gregg F
authors.initials: GF
authors.lastname: Keaney
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.affiliation: Eisai, Inc., Andover, MA 01810, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Kumar
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.affiliation: Eisai, Inc., Andover, MA 01810, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: MacKenzie
authors.affiliation: Eisai, Inc., Andover, MA 01810, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Matijevic
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Mizui
authors.affiliation: Eisai, Inc., Andover, MA 01810, USA.
authors.forename: Khin
authors.initials: K
authors.lastname: Myint
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Park
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Puyang
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Selvaraj
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Thomas
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsai
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: John Y
authors.initials: JY
authors.lastname: Wang
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Department of Hematology/Oncology, Weill Cornell Medical College, New York, NY 10020, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Yu
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.affiliation: H3 Biomedicine, Inc., Cambridge, MA 02139, USA. Electronic address: silvia_buonamici@h3biomedicine.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Buonamici
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*; D059365:Nonsense Mediated mRNA Decay; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human