Distinct and evolutionary conserved structural features of the human nuclear exosome complex

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• The nuclear exosome complex is crucial for RNA processing and degradation in human cells.
• Previous mechanistic studies primarily utilized the yeast exosome system.
• Understanding the human exosome structure and function is vital for human biology.

Purpose of the Study:

• To reconstitute and characterize the 14-subunit human nuclear exosome complex.
• To elucidate the structural basis of RNA channel function in the human exosome.
• To compare the human exosome structure with its yeast and bacterial counterparts.

Main Methods:

• Reconstitution of a recombinant 14-subunit human nuclear exosome complex.
• Biochemical assays to determine RNA channel properties.
• Cryo-electron microscopy (cryo-EM) to determine the structure of the core and holo-complexes.

Main Results:

• The human exosome possesses a longer RNA channel compared to the yeast exosome.
• Cryo-EM structure reveals the hDIS3 exoribonuclease contributes to the RNA channel via an open conformation.
• The holo-complex structure shows nuclear cofactors positioning the hMTR4 helicase, indicating conserved mechanisms across eukaryotes.

Conclusions:

• The human nuclear exosome exhibits distinct structural features, including an extended RNA channel.
• Structural insights into hDIS3 and hMTR4 interactions provide a mechanistic basis for RNA processing.
• The study highlights conserved structural organization of the nuclear exosome from lower to higher eukaryotes.