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Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer

The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DA...

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Autores principales: Han, Jian, An, Omer, Ren, Xi, Song, Yangyang, Tang, Sze Jing, Shen, Haoqing, Ke, Xinyu, Ng, Vanessa Hui En, Tay, Daryl Jin Tai, Tan, Hui Qing, Kappei, Dennis, Yang, Henry, Chen, Leilei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980049/
https://www.ncbi.nlm.nih.gov/pubmed/35379802
http://dx.doi.org/10.1038/s41467-022-29400-7
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author Han, Jian
An, Omer
Ren, Xi
Song, Yangyang
Tang, Sze Jing
Shen, Haoqing
Ke, Xinyu
Ng, Vanessa Hui En
Tay, Daryl Jin Tai
Tan, Hui Qing
Kappei, Dennis
Yang, Henry
Chen, Leilei
author_facet Han, Jian
An, Omer
Ren, Xi
Song, Yangyang
Tang, Sze Jing
Shen, Haoqing
Ke, Xinyu
Ng, Vanessa Hui En
Tay, Daryl Jin Tai
Tan, Hui Qing
Kappei, Dennis
Yang, Henry
Chen, Leilei
author_sort Han, Jian
collection PubMed
description The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development.
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spelling pubmed-89800492022-04-20 Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer Han, Jian An, Omer Ren, Xi Song, Yangyang Tang, Sze Jing Shen, Haoqing Ke, Xinyu Ng, Vanessa Hui En Tay, Daryl Jin Tai Tan, Hui Qing Kappei, Dennis Yang, Henry Chen, Leilei Nat Commun Article The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development. Nature Publishing Group UK 2022-04-04 /pmc/articles/PMC8980049/ /pubmed/35379802 http://dx.doi.org/10.1038/s41467-022-29400-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Han, Jian
An, Omer
Ren, Xi
Song, Yangyang
Tang, Sze Jing
Shen, Haoqing
Ke, Xinyu
Ng, Vanessa Hui En
Tay, Daryl Jin Tai
Tan, Hui Qing
Kappei, Dennis
Yang, Henry
Chen, Leilei
Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title_full Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title_fullStr Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title_full_unstemmed Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title_short Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer
title_sort multilayered control of splicing regulatory networks by dap3 leads to widespread alternative splicing changes in cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8980049/
https://www.ncbi.nlm.nih.gov/pubmed/35379802
http://dx.doi.org/10.1038/s41467-022-29400-7
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