A functional connection between the Microprocessor and a variant NEXT complex

Area of Science:

• Molecular Biology
• RNA Biology
• Gene Regulation

Background:

• Primary microRNAs (miRNAs) are processed by the Microprocessor complex (DROSHA-DGCR8) in mammalian cells.
• The RNA exosome pathway degrades various RNA substrates, but its specific targeting mechanisms are still being elucidated.

Purpose of the Study:

• To investigate the fate of 5' flanking regions generated after Microprocessor cleavage of primary miRNAs.
• To identify the protein complexes involved in the turnover of these RNA fragments and other structured RNAs.

Main Methods:

• Biochemical assays to study protein-RNA interactions.
• Mutagenesis studies to probe the function of specific protein domains.
• Analysis of RNA processing and degradation in mouse embryonic stem cells (mESCs).

Main Results:

• The nuclear exosome targeting (NEXT) complex, specifically its ZCCHC8 component, physically interacts with DGCR8.
• A variant NEXT complex, comprising MTR4 and ZCCHC8 but lacking RBM7, is responsible for targeting stem-loop containing RNAs, including those derived from Microprocessor activity.
• This MTR4-ZCCHC8 complex also targets other structured RNAs, such as those from enhancers, demonstrating substrate flexibility.

Conclusions:

• The MTR4-ZCCHC8 NEXT complex links with Microprocessor (DGCR8/DROSHA) to degrade specific RNA structures.
• RNA structural context dictates targeting by either the RBM7-containing or DGCR8-linked NEXT complex, revealing a sophisticated RNA surveillance mechanism.