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The Supraspliceosome - A Multi-Task Machine for Regulated Pre-mRNA Processing in the Cell Nucleus.

Kinneret Shefer1, Joseph Sperling1, Ruth Sperling2

  • 1Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.

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|November 20, 2014
PubMed
Summary

The supraspliceosome, a large nuclear RNP machine, coordinates multiple pre-mRNA processing steps including splicing, RNA editing, and quality control. This complex machine is crucial for regulating gene expression and is implicated in human diseases.

Keywords:
Alternative splicingIntronic microRNA biogenesisPre-mRNA splicingRiponucleoproteins (RNPs)Suppression of splicingU snRNPs

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Pre-mRNA splicing in mammalian cells occurs within a large, dynamic ribonucleoprotein (RNP) complex called the supraspliceosome.
  • The supraspliceosome comprises four active native spliceosomes linked by pre-mRNA and contains splicing factors, U snRNPs, and RNA processing enzymes.

Purpose of the Study:

  • To elucidate the structure and function of the native spliceosome and supraspliceosome.
  • To understand the coordination of diverse pre-mRNA processing events within this nuclear machine.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine native spliceosome structure at 20 Å resolution.
  • In-silico studies to analyze the spatial arrangement of U snRNPs within the spliceosome.

Main Results:

  • The native spliceosome structure revealed a unique spatial organization of the five U snRNPs, primarily in the large subunit.
  • Supraspliceosomes integrate 5'/3'-end processing, RNA editing (ADAR1/2), splicing, and microRNA processing.
  • A quality control mechanism, suppression of splicing (SOS), was identified for regulating intronic splice sites.

Conclusions:

  • The supraspliceosome acts as a central platform coordinating multiple pre-mRNA processing steps, including splicing and RNA editing.
  • Dysregulation of these processing activities within the supraspliceosome is linked to human diseases and cancer.
  • The supraspliceosome is a master regulator of nuclear pre-mRNA processing.