UPF1 promotes rapid degradation of m⁶A-containing RNAs

Area of Science:

• Molecular Biology
• RNA Biology
• Biochemistry

Background:

• N-methyladenosine (m⁶A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), influencing RNA processing and metabolism.
• YTHDF2 is an m⁶A-binding protein that promotes the degradation of m⁶A-modified RNAs (m⁶A RNAs).

Purpose of the Study:

• To investigate the interaction between UPF1 and YTHDF2 and its role in m⁶A RNA degradation.
• To elucidate the molecular mechanisms underlying UPF1-mediated m⁶A RNA decay.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions.
• In vitro assays to assess UPF1 ATPase/helicase activities.
• Transcriptome-wide analyses to identify destabilized m⁶A RNAs.
• RNA degradation assays.

Main Results:

• UPF1 directly interacts with YTHDF2, leading to the rapid degradation of m⁶A RNAs.
• UPF1-mediated degradation requires the N-terminal region of YTHDF2 (residues 101-168), UPF1's ATPase/helicase activities, and its interaction with PNRC2.
• UPF1 enhances the destabilization of YTHDF2-bound mRNAs not targeted by HRSP12-RNase P/MRP endoribonucleolytic cleavage.

Conclusions:

• UPF1 plays a critical role in the degradation of m⁶A RNAs by interacting with YTHDF2.
• The findings reveal a dynamic and complex regulatory network governing m⁶A RNA stability.
• This study highlights the multifaceted involvement of UPF1 in mRNA decay pathways.