Splicing quality control mediated by DHX15 and its G-patch activator SUGP1.

Area of Science:

• Molecular Biology
• RNA Biology
• Gene Expression Regulation

Background:

• Pre-mRNA splicing is a complex process essential for gene expression.
• Quality control (QC) mechanisms surveil splicing at various stages.
• The DExH-box helicase DHX15 is known for its role in spliceosome disassembly.

Purpose of the Study:

• To investigate the splicing quality control (QC) function of DHX15 in human cells.
• To identify factors that regulate DHX15's role in splicing fidelity.
• To elucidate the mechanism by which DHX15 ensures accurate splicing.

Main Methods:

• Rapid protein depletion experiments to isolate direct effects.
• Analysis of nascent and mature RNA to assess splicing outcomes.
• Biochemical assays to study protein-protein interactions and enzyme activity.

Main Results:

• DHX15 exhibits a widespread splicing QC function in human cells.
• DHX15 represses suboptimal introns, including those with weak splice sites, multiple branch points, and cryptic introns.
• SUGP1 acts as a G-patch factor that activates DHX15's splicing QC function via its ULM domain and DHX15's ATPase activity.

Conclusions:

• DHX15 plays a significant role in promoting splicing fidelity.
• The interaction between SUGP1 and DHX15 is critical for activating DHX15's splicing QC function.
• A model is proposed where SUGP1 recruits and activates DHX15 for effective splicing surveillance.