Multilayered Control of Splicing Regulatory Networks by DAP3 Leads to Widespread Alternative Splicing Changes in Cancer. (Nat Commun, Apr 22)

Jian Han¹, Omer An², Xi Ren², Yangyang Song², Sze Jing Tang², Haoqing Shen², Xinyu Ke², Vanessa Hui En Ng², Daryl Jin Tai Tay², Hui Qing Tan³, Dennis Kappei^2 4 5, Henry Yang², Leilei Chen^6 7 8

Affiliations

¹Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. csihj@nus.edu.sg.
²Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
³Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117549, Singapore.
⁴Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
⁵NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
⁶Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. polly_chen@nus.edu.sg.
⁷NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore. polly_chen@nus.edu.sg.
⁸Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore. polly_chen@nus.edu.sg.

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.

Multilayered Control of Splicing Regulatory Networks by DAP3 Leads to Widespread Alternative Splicing Changes in Cancer. (Nat Commun, Apr 22)

Affiliations

Abstract

CSI Web Experience Survey Form

Please Rate Your Satisfaction