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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
10:06

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells

Hui Li1, Jinglan Wang, Gil Mor

  • 1Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.

Science (New York, N.Y.)
|September 6, 2008
PubMed

Insights

Normal endometrial cells produce a JAZF1-JJAZ1 fusion protein via RNA trans-splicing, which has anti-apoptotic activity. This finding suggests some gene fusions may promote cancer by constitutively expressing normally transient chimeric products.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Gene fusions are common in human tumors, typically viewed as abnormal, tumor-specific products driving cancer growth.
  • The prevailing hypothesis suggests chimeric transcripts and proteins confer a growth or survival advantage to tumor cells.

Purpose of the Study:

  • To investigate the origin and function of the JAZF1-JJAZ1 chimeric RNA and protein.
  • To determine if normally occurring trans-splicing events could explain gene fusions found in tumors.

Main Methods:

  • Analysis of RNA transcripts in normal endometrial stromal cells.
  • Identification of chimeric RNA molecules.
  • Protein expression analysis and functional assays for anti-apoptotic activity.
  • Comparison of tumor-derived gene fusions with naturally occurring chimeric products.

Main Results:

  • Normal endometrial stromal cells express a chimeric RNA (JAZF1-JJAZ1) formed by trans-splicing of JAZF1 and JJAZ1 precursor messenger RNAs.
  • This chimeric RNA is translated into a JAZF1-JJAZ1 protein exhibiting anti-apoptotic activity.
  • The naturally occurring JAZF1-JJAZ1 RNA and protein are identical to those produced by gene fusions in endometrial stromal tumors.

Conclusions:

  • Physiologically regulated trans-splicing can generate chimeric gene products with functional significance, such as anti-apoptotic activity.
  • Constitutive expression of these normally transient chimeric products, as seen in tumors, may be a pro-neoplastic mechanism.
  • This challenges the view that all tumor-associated gene fusions are solely abnormal, aberrant events.

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