Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.
Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.
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DOI：
10.1371/journal.pcbi.1004105
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发表时间：
2015-03
影响因子：
4.3
通讯作者：
Frazer KA
中科院分区：
文献类型：
--
作者：
DeBoever C;Ghia EM;Shepard PJ;Rassenti L;Barrett CL;Jepsen K;Jamieson CH;Carson D;Kipps TJ;Frazer KA
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. A key goal of cancer genomics studies is to identify genes that are recurrently mutated at a rate above background and likely contribute to cancer development. Many such recurrently mutated genes have been identified over the last few years, but we often do not know the underlying mechanisms by which they contribute to cancer growth. Unexpectedly, several genes in the spliceosome, the collection of RNAs and proteins that remove introns from transcribed RNAs, are recurrently mutated in different cancers. Here, we have examined mutations in the splicing factor SF3B1, a key component of the spliceosome, and identified a global splicing defect present in different cancers with SF3B1 mutations by comparing the expression of splice junctions using generalized linear models. While prior studies have reported a limited number of aberrant splicing events in SF3B1-mutated cancers, we have established that SF3B1 mutations are associated with usage of hundreds of atypical splice sites at the 3’ end of the intron. We have identified nucleotide sequence requirements for these cryptic splice sites that are consistent with a proposed mechanistic model. These findings greatly expand our understanding of the effect of SF3B1 mutations on splicing and provide new targets for determining the oncogenic effect of SF3B1 mutations.
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影响因子：
4.3
作者：
Corvelo A;Hallegger M;Smith CW;Eyras E
通讯作者：
Eyras E
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
4.8
作者：
Kaizuka, Takeshi;Hara, Taichi;Mizushima, Noboru
通讯作者：
Mizushima, Noboru