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Nuclear cyclophilins affect spliceosome assembly and function in vitro.

B M Adams1, Miranda N Coates1, S RaElle Jackson2

  • 1Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, CA 95064, U.S.A.

The Biochemical Journal
|May 14, 2015
PubMed
Summary
This summary is machine-generated.

Nuclear cyclophilins are key regulators of the human spliceosome. This study identifies four nuclear cyclophilins that significantly impact pre-mRNA splicing in vitro, offering new avenues for therapeutic development.

Keywords:
nuclear cyclophilinspre-messenger RNA (mRNA) splicingspliceosome

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Cyclophilins are proline-binding proteins catalyzing cis/trans isomerization.
  • Human cells express 17 cyclophilin family members with diverse localizations.
  • Eight nuclear cyclophilins are associated with spliceosomal complexes, but their functions are unknown.

Purpose of the Study:

  • To investigate the functional roles of nuclear cyclophilins within the human spliceosome.
  • To determine if nuclear cyclophilins act as splicing factors.
  • To establish a foundation for small molecule-based modulation of pre-mRNA splicing.

Main Methods:

  • Adaptation of three established in vitro pre-mRNA splicing assays.
  • Qualitative and quantitative analysis of splicing activity.
  • Dose-dependent effect assessment of nuclear cyclophilins on splicing.

Main Results:

  • Four out of eight spliceosome-associated cyclophilins significantly affect in vitro pre-mRNA splicing.
  • The observed effects on splicing are dose-dependent and unique to each cyclophilin.
  • At least half of the nuclear cyclophilins function as regulatory factors of spliceosome activity in vitro.

Conclusions:

  • Provides the first quantifiable evidence of nuclear cyclophilins acting as splicing factors.
  • Demonstrates that nuclear cyclophilins are regulatory components of spliceosome function.
  • Establishes a novel approach for future research into small molecule-driven modulation of pre-mRNA splicing.