How Is Precursor Messenger RNA Spliced by the Spliceosome?

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• RNA splicing is a fundamental biological process involving precursor messenger RNA (pre-mRNA) maturation.
• The spliceosome complex mediates pre-mRNA splicing, a process crucial for gene expression.
• Decades of research have elucidated splicing mechanisms, with recent atomic-resolution structural studies providing key insights.

Purpose of the Study:

• To delineate the mechanism of RNA splicing through structural and biochemical investigations of the spliceosome.
• To understand the roles of conserved RNA elements, catalytic metal ions, and protein components in spliceosome function.
• To compare the conserved organization of the spliceosome and its active site between human and yeast.

Main Methods:

• Biochemical and genetic investigations over four decades.
• Atomic-resolution structural studies of the intact spliceosome since 2015.
• Comparative analysis of spliceosome organization in human and yeast.

Main Results:

• The spliceosome is a protein-orchestrated metalloribozyme.
• Conserved small nuclear RNA (snRNA) elements form the catalytic active site with two metal ions.
• Proteins stabilize snRNA conformation, drive remodeling, orchestrate RNA movement, and facilitate splicing.

Conclusions:

• The spliceosome's conserved structure and active site configuration in human and yeast highlight fundamental mechanisms of RNA splicing.
• Structural insights reveal how conserved snRNA elements and catalytic metal ions mediate intron removal and exon ligation.
• Protein components play critical roles in stabilizing, remodeling, and orchestrating the spliceosome's catalytic activity.