Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.

TitleTranscriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.
Publication TypeJournal Article
Year of Publication2015
AuthorsDeBoever C, Ghia EM, Shepard PJ, Rassenti L, Barrett CL, Jepsen K, Jamieson CHM, Carson D, Kipps TJ, Frazer KA
JournalPLoS Comput Biol
Volume11
Issue3
Paginatione1004105
Date Published2015 Mar
ISSN1553-7358
Abstract

Mutations in the splicing factor SF3B1 are found in several cancer types and have been associated with various splicing defects. Using transcriptome sequencing data from chronic lymphocytic leukemia, breast cancer and uveal melanoma tumor samples, we show that hundreds of cryptic 3' splice sites (3'SSs) are used in cancers with SF3B1 mutations. We define the necessary sequence context for the observed cryptic 3' SSs and propose that cryptic 3'SS selection is a result of SF3B1 mutations causing a shift in the sterically protected region downstream of the branch point. While most cryptic 3'SSs are present at low frequency (<10%) relative to nearby canonical 3'SSs, we identified ten genes that preferred out-of-frame cryptic 3'SSs. We show that cancers with mutations in the SF3B1 HEAT 5-9 repeats use cryptic 3'SSs downstream of the branch point and provide both a mechanistic model consistent with published experimental data and affected targets that will guide further research into the oncogenic effects of SF3B1 mutation.

DOI10.1371/journal.pcbi.1004105
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/25768983?dopt=Abstract
Alternate JournalPLoS Comput. Biol.
PubMed ID25768983
PubMed Central IDPMC4358997
Grant List1R21CA152613 / CA / NCI NIH HHS / United States
P01 CA081534 / CA / NCI NIH HHS / United States
P01CA81534 / CA / NCI NIH HHS / United States
T32 CA121938 / CA / NCI NIH HHS / United States
Track(s): 
Bioinformatics and Systems Biology