Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Kienan I. Savage; Julia J. Gorski; Eliana M. Barros; Gareth W. Irwin; Lorenzo Manti; Alexander J. Powell; Andrea Pellagatti; Natalia Lukashchuk; Dennis J. McCance; W. Glenn McCluggage; Giuseppe Schettino; Manuel Salto-Tellez; Jacqueline  Boultwood; Derek J. Richard; Simon S. McDade; D. Paul Harkin

doi:10.1016/j.molcel.2014.03.021

Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Kienan I. Savage^*, Julia J. Gorski, Eliana M. Barros, Gareth W. Irwin, Lorenzo Manti, Alexander J. Powell, Andrea Pellagatti, Natalia Lukashchuk, Dennis J. McCance, W. Glenn McCluggage, Giuseppe Schettino, Manuel Salto-Tellez, Jacqueline Boultwood, Derek J. Richard , Simon S. McDade, D. Paul Harkin

^*Corresponding author for this work

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Abstract

Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

Original language	English
Pages (from-to)	445-459
Number of pages	15
Journal	Molecular Cell
Volume	54
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2014.03.021
Publication status	Published - 08 May 2014

Keywords

BRCA1, DNA damage, genome stability, DNA repair, mRNA splicing

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Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability
Copyright © 2014 The Authors. This is an open access article licensed under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
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Cancer Discovery (journal) - editorial "BRCA1-MEDIATED mRNA SPLICING MAINTAINS GENOME STABILITY"
Savage, K. & Harkin, P.
02/06/2014
1 item of Media coverage
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Kienan Savage
- k.savagequb.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Professor
- Patrick G Johnston Centre for Cancer Research
Person: Academic

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Savage, K. I., Gorski, J. J., Barros, E. M., Irwin, G. W., Manti, L., Powell, A. J., Pellagatti, A., Lukashchuk, N., McCance, D. J., McCluggage, W. G., Schettino, G., Salto-Tellez, M., Boultwood, J., Richard , D. J., McDade, S. S., & Harkin, D. P. (2014). Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability. Molecular Cell, 54(3), 445-459. https://doi.org/10.1016/j.molcel.2014.03.021

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title = "Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability",

abstract = "Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.",

keywords = "BRCA1, DNA damage, genome stability, DNA repair, mRNA splicing ",

author = "Savage, {Kienan I.} and Gorski, {Julia J.} and Barros, {Eliana M.} and Irwin, {Gareth W.} and Lorenzo Manti and Powell, {Alexander J.} and Andrea Pellagatti and Natalia Lukashchuk and McCance, {Dennis J.} and McCluggage, {W. Glenn} and Giuseppe Schettino and Manuel Salto-Tellez and Jacqueline Boultwood and Richard, {Derek J.} and McDade, {Simon S.} and Harkin, {D. Paul}",

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Savage, KI, Gorski, JJ, Barros, EM, Irwin, GW, Manti, L, Powell, AJ, Pellagatti, A, Lukashchuk, N, McCance, DJ, McCluggage, WG, Schettino, G, Salto-Tellez, M, Boultwood, J, Richard , DJ, McDade, SS & Harkin, DP 2014, 'Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability', Molecular Cell, vol. 54, no. 3, pp. 445-459. https://doi.org/10.1016/j.molcel.2014.03.021

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T1 - Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

AU - Savage, Kienan I.

AU - Gorski, Julia J.

AU - Barros, Eliana M.

AU - Irwin, Gareth W.

AU - Manti, Lorenzo

AU - Powell, Alexander J.

AU - Pellagatti, Andrea

AU - Lukashchuk, Natalia

AU - McCance, Dennis J.

AU - McCluggage, W. Glenn

AU - Schettino, Giuseppe

AU - Salto-Tellez, Manuel

AU - Boultwood, Jacqueline

AU - Richard , Derek J.

AU - McDade, Simon S.

AU - Harkin, D. Paul

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N2 - Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

AB - Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

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DO - 10.1016/j.molcel.2014.03.021

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SN - 1097-4164

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SP - 445

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JO - Molecular Cell

JF - Molecular Cell

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Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Abstract

Keywords

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Cancer Discovery (journal) - editorial "BRCA1-MEDIATED mRNA SPLICING MAINTAINS GENOME STABILITY"

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