Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.
|Title||Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||DeBoever C, Ghia EM, Shepard PJ, Rassenti L, Barrett CL, Jepsen K, Jamieson CHM, Carson D, Kipps TJ, Frazer KA|
|Journal||PLoS Comput Biol|
|Date Published||2015 Mar|
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.
|Alternate Journal||PLoS Comput. Biol.|
|PubMed Central ID||PMC4358997|
|Grant List||1R21CA152613 / 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