SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates

Adenosine-to-inosine (A-to-I) RNA editing displays diverse spatial patterns across different tissues. However, the human genome encodes only two catalytically active editing enzymes (ADAR1 and ADAR2), suggesting that other regulatory factors help shape the editing landscape. Here, we show that the s...

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Main Authors: Zhang, Fan, Srinivasan, Harini, Shanmugam, Raghuvaran, Charles Richard, John Lalith, Zhang, Xiujun, Liu, Kaiwen I., Woo, Cheok Wei A., Chua, Zi Hao M., Buschdorf, Jan Paul, Meaney, Michael J., Tan, Meng How
Other Authors: School of Chemical and Biomedical Engineering
Format: Article
Language:English
Published: 2019
Subjects:
RNA
Online Access:https://hdl.handle.net/10356/103742
http://hdl.handle.net/10220/47392
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1037422023-12-29T06:52:32Z SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates Zhang, Fan Srinivasan, Harini Shanmugam, Raghuvaran Charles Richard, John Lalith Zhang, Xiujun Liu, Kaiwen I. Woo, Cheok Wei A. Chua, Zi Hao M. Buschdorf, Jan Paul Meaney, Michael J. Tan, Meng How School of Chemical and Biomedical Engineering RNA RNA-protein Complexes DRNTU::Engineering::Chemical engineering::Biochemical engineering Adenosine-to-inosine (A-to-I) RNA editing displays diverse spatial patterns across different tissues. However, the human genome encodes only two catalytically active editing enzymes (ADAR1 and ADAR2), suggesting that other regulatory factors help shape the editing landscape. Here, we show that the splicing factor SRSF9 selectively controls the editing of many brain-specific sites in primates. SRSF9 is more lowly expressed in the brain than in non-brain tissues. Gene perturbation experiments and minigene analysis of candidate sites demonstrated that SRSF9 could robustly repress A-to-I editing by ADAR2. We found that SRSF9 biochemically interacted with ADAR2 in the nucleus via its RRM2 domain. This interaction required the presence of the RNA substrate and disrupted the formation of ADAR2 dimers. Transcriptome-wide location analysis and RNA sequencing revealed 1328 editing sites that are controlled directly by SRSF9. This regulon is significantly enriched for brain-specific sites. We further uncovered a novel motif in the ADAR2-dependent SRSF9 binding sites and provided evidence that the splicing factor prevents loss of cell viability by inhibiting ADAR2-mediated editing of genes involved in proteostasis, energy metabolism, the cell cycle and DNA repair. Collectively, our results highlight the importance of SRSF9 as an editing regulator and suggest potential roles for other splicing factors. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) Published version 2019-01-07T01:31:23Z 2019-12-06T21:19:14Z 2019-01-07T01:31:23Z 2019-12-06T21:19:14Z 2018 Journal Article Shanmugam, R., Zhang, F., Srinivasan, H., Charles Richard, J. L., Liu, K. I., Zhang, X., . . . Tan, M. H. (2018). SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates. Nucleic Acids Research, 46(14), 7379-7395. doi:10.1093/nar/gky615 0305-1048 https://hdl.handle.net/10356/103742 http://hdl.handle.net/10220/47392 10.1093/nar/gky615 en Nucleic Acids Research © 2018 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 17 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic RNA
RNA-protein Complexes
DRNTU::Engineering::Chemical engineering::Biochemical engineering
spellingShingle RNA
RNA-protein Complexes
DRNTU::Engineering::Chemical engineering::Biochemical engineering
Zhang, Fan
Srinivasan, Harini
Shanmugam, Raghuvaran
Charles Richard, John Lalith
Zhang, Xiujun
Liu, Kaiwen I.
Woo, Cheok Wei A.
Chua, Zi Hao M.
Buschdorf, Jan Paul
Meaney, Michael J.
Tan, Meng How
SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
description Adenosine-to-inosine (A-to-I) RNA editing displays diverse spatial patterns across different tissues. However, the human genome encodes only two catalytically active editing enzymes (ADAR1 and ADAR2), suggesting that other regulatory factors help shape the editing landscape. Here, we show that the splicing factor SRSF9 selectively controls the editing of many brain-specific sites in primates. SRSF9 is more lowly expressed in the brain than in non-brain tissues. Gene perturbation experiments and minigene analysis of candidate sites demonstrated that SRSF9 could robustly repress A-to-I editing by ADAR2. We found that SRSF9 biochemically interacted with ADAR2 in the nucleus via its RRM2 domain. This interaction required the presence of the RNA substrate and disrupted the formation of ADAR2 dimers. Transcriptome-wide location analysis and RNA sequencing revealed 1328 editing sites that are controlled directly by SRSF9. This regulon is significantly enriched for brain-specific sites. We further uncovered a novel motif in the ADAR2-dependent SRSF9 binding sites and provided evidence that the splicing factor prevents loss of cell viability by inhibiting ADAR2-mediated editing of genes involved in proteostasis, energy metabolism, the cell cycle and DNA repair. Collectively, our results highlight the importance of SRSF9 as an editing regulator and suggest potential roles for other splicing factors.
author2 School of Chemical and Biomedical Engineering
author_facet School of Chemical and Biomedical Engineering
Zhang, Fan
Srinivasan, Harini
Shanmugam, Raghuvaran
Charles Richard, John Lalith
Zhang, Xiujun
Liu, Kaiwen I.
Woo, Cheok Wei A.
Chua, Zi Hao M.
Buschdorf, Jan Paul
Meaney, Michael J.
Tan, Meng How
format Article
author Zhang, Fan
Srinivasan, Harini
Shanmugam, Raghuvaran
Charles Richard, John Lalith
Zhang, Xiujun
Liu, Kaiwen I.
Woo, Cheok Wei A.
Chua, Zi Hao M.
Buschdorf, Jan Paul
Meaney, Michael J.
Tan, Meng How
author_sort Zhang, Fan
title SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
title_short SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
title_full SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
title_fullStr SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
title_full_unstemmed SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates
title_sort srsf9 selectively represses adar2-mediated editing of brain-specific sites in primates
publishDate 2019
url https://hdl.handle.net/10356/103742
http://hdl.handle.net/10220/47392
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