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

Jian Han (), Omer An, Xi Ren, Yangyang Song, Sze Jing Tang, Haoqing Shen, Xinyu Ke, Vanessa Hui En Ng, Daryl Jin Tai Tay, Hui Qing Tan, Dennis Kappei, Henry Yang and Leilei Chen ()
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Jian Han: National University of Singapore
Omer An: National University of Singapore
Xi Ren: National University of Singapore
Yangyang Song: National University of Singapore
Sze Jing Tang: National University of Singapore
Haoqing Shen: National University of Singapore
Xinyu Ke: National University of Singapore
Vanessa Hui En Ng: National University of Singapore
Daryl Jin Tai Tay: National University of Singapore
Hui Qing Tan: National University of Singapore
Dennis Kappei: National University of Singapore
Henry Yang: National University of Singapore
Leilei Chen: National University of Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29400-7

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