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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in

Jian Han1, Omer An2, Xi Ren2

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. csihj@nus.edu.sg.

Nature Communications
|April 5, 2022
PubMed

Insights

Cancer-associated protein DAP3 acts as a splicing regulator, influencing gene expression through ribonucleoprotein complexes and splicing factor modulation. DAP3-driven mis-splicing in multiple cancers predicts poor prognosis and contributes to tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • RNA Biology

Background:

  • Alternative splicing is dynamically regulated by RNA binding proteins (RBPs).
  • Dysregulation of splicing regulatory RBPs is linked to cancer development.
  • The role of DAP3 in splicing regulation within cancer remains largely uncharacterized.

Purpose of the Study:

  • To investigate DAP3 as a novel splicing regulatory RBP in cancer.
  • To elucidate the mechanisms by which DAP3 influences alternative splicing in cancer.
  • To assess the pan-cancer relevance and prognostic implications of DAP3-modulated splicing.

Main Methods:

  • Identification of DAP3 as a splicing regulatory RBP.
  • Analysis of ribonucleoprotein complex formation and substrate-specific splicing changes.
  • Pan-cancer analysis of alternative splicing across 33 TCGA cancer types.
  • Functional investigation of WSB1 splicing in tumorigenesis.

Main Results:

  • DAP3 is frequently overexpressed in cancer and functions as a splicing regulatory RBP.
  • DAP3 modulates splicing through direct and indirect mechanisms, affecting numerous splicing factors.
  • DAP3-modulated mis-splicing events were identified in multiple cancers, with some predicting poor prognosis.
  • Functional studies demonstrated a causal link between DAP3-modulated WSB1 splicing and tumorigenesis.

Conclusions:

  • DAP3 plays a critical role in coordinating splicing regulatory networks in cancer.
  • DAP3-mediated alternative splicing contributes to cancer development and progression.
  • DAP3 represents a potential therapeutic target for modulating splicing in cancer.

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