Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point

Rachel B. Darman; Michael Seiler; Anant A. Agrawal; Kian H. Lim; Shouyong Peng; Daniel Aird; Suzanna L. Bailey; Erica B. Bhavsar; Betty Chan; Simona Colla; Laura Corson; Jacob Feala; Peter Fekkes; Kana Ichikawa; Gregg F. Keaney; Linda Lee; Pavan Kumar; Kaiko Kunii; Crystal MacKenzie; Mark Matijevic; Yoshiharu Mizui; Khin Myint; Eun Sun Park; Xiaoling Puyang; Anand Selvaraj; Michael P. Thomas; Jennifer Tsai; John Y. Wang; Markus Warmuth; Hui Yang; Ping Zhu; Guillermo Garcia-Manero; Richard R. Furman; Lihua Yu; Peter G. Smith; Silvia Buonamici

doi:10.1016/j.celrep.2015.09.053

Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point

Rachel B. Darman, Michael Seiler, Anant A. Agrawal, Kian H. Lim, Shouyong Peng, Daniel Aird, Suzanna L. Bailey, Erica B. Bhavsar, Betty Chan, Simona Colla, Laura Corson, Jacob Feala, Peter Fekkes, Kana Ichikawa, Gregg F. Keaney, Linda Lee, Pavan Kumar, Kaiko Kunii, Crystal MacKenzie, Mark MatijevicYoshiharu Mizui, Khin Myint, Eun Sun Park, Xiaoling Puyang, Anand Selvaraj, Michael P. Thomas, Jennifer Tsai, John Y. Wang, Markus Warmuth, Hui Yang, Ping Zhu, Guillermo Garcia-Manero, Richard R. Furman, Lihua Yu, Peter G. Smith, Silvia Buonamici

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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.

Original language	English (US)
Pages (from-to)	1033-1045
Number of pages	13
Journal	Cell Reports
Volume	13
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2015.09.053
State	Published - Nov 3 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Darman, R. B., Seiler, M., Agrawal, A. A., Lim, K. H., Peng, S., Aird, D., Bailey, S. L., Bhavsar, E. B., Chan, B., Colla, S., Corson, L., Feala, J., Fekkes, P., Ichikawa, K., Keaney, G. F., Lee, L., Kumar, P., Kunii, K., MacKenzie, C., ... Buonamici, S. (2015). Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point. Cell Reports, 13(5), 1033-1045. https://doi.org/10.1016/j.celrep.2015.09.053

Darman, RB, Seiler, M, Agrawal, AA, Lim, KH, Peng, S, Aird, D, Bailey, SL, Bhavsar, EB, Chan, B, Colla, S, Corson, L, Feala, J, Fekkes, P, Ichikawa, K, Keaney, GF, Lee, L, Kumar, P, Kunii, K, MacKenzie, C, Matijevic, M, Mizui, Y, Myint, K, Park, ES, Puyang, X, Selvaraj, A, Thomas, MP, Tsai, J, Wang, JY, Warmuth, M, Yang, H, Zhu, P, Garcia-Manero, G, Furman, RR, Yu, L, Smith, PG & Buonamici, S 2015, 'Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point', Cell Reports, vol. 13, no. 5, pp. 1033-1045. https://doi.org/10.1016/j.celrep.2015.09.053

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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.",

author = "Darman, {Rachel B.} and Michael Seiler and Agrawal, {Anant A.} and Lim, {Kian H.} and Shouyong Peng and Daniel Aird and Bailey, {Suzanna L.} and Bhavsar, {Erica B.} and Betty Chan and Simona Colla and Laura Corson and Jacob Feala and Peter Fekkes and Kana Ichikawa and Keaney, {Gregg F.} and Linda Lee and Pavan Kumar and Kaiko Kunii and Crystal MacKenzie and Mark Matijevic and Yoshiharu Mizui and Khin Myint and Park, {Eun Sun} and Xiaoling Puyang and Anand Selvaraj and Thomas, {Michael P.} and Jennifer Tsai and Wang, {John Y.} and Markus Warmuth and Hui Yang and Ping Zhu and Guillermo Garcia-Manero and Furman, {Richard R.} and Lihua Yu and Smith, {Peter G.} and Silvia Buonamici",

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doi = "10.1016/j.celrep.2015.09.053",

language = "English (US)",

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AU - Darman, Rachel B.

AU - Seiler, Michael

AU - Agrawal, Anant A.

AU - Lim, Kian H.

AU - Peng, Shouyong

AU - Aird, Daniel

AU - Bailey, Suzanna L.

AU - Bhavsar, Erica B.

AU - Chan, Betty

AU - Colla, Simona

AU - Corson, Laura

AU - Feala, Jacob

AU - Fekkes, Peter

AU - Ichikawa, Kana

AU - Keaney, Gregg F.

AU - Lee, Linda

AU - Kumar, Pavan

AU - Kunii, Kaiko

AU - MacKenzie, Crystal

AU - Matijevic, Mark

AU - Mizui, Yoshiharu

AU - Myint, Khin

AU - Park, Eun Sun

AU - Puyang, Xiaoling

AU - Selvaraj, Anand

AU - Thomas, Michael P.

AU - Tsai, Jennifer

AU - Wang, John Y.

AU - Warmuth, Markus

AU - Yang, Hui

AU - Zhu, Ping

AU - Garcia-Manero, Guillermo

AU - Furman, Richard R.

AU - Yu, Lihua

AU - Smith, Peter G.

AU - Buonamici, Silvia

PY - 2015/11/3

Y1 - 2015/11/3

N2 - 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.

AB - 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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Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3' Splice Site Selection through Use of a Different Branch Point

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