Multiple E3 ligases control tankyrase stability and function.

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Tankyrases (TNKS) are ADP-ribosyltransferases crucial for telomere cohesion and Wnt/β-catenin signaling.
• Tankyrase activity is regulated by poly(ADP-ribose) (PAR) and PAR-binding E3 ligases like RNF146, which targets PARylated proteins for degradation.
• Small molecule tankyrase inhibitors are under investigation for cancer therapies.

Approach:

• Investigated novel interactions between tankyrase and RING-UIM (Ubiquitin-Interacting Motif) E3 ligases (RNF114, RNF166).
• Assessed the effect of RING-UIM E3 ligases on tankyrase ubiquitylation and stability.
• Identified PAR-binding E3 ligases that ubiquitylate tankyrase, influencing its stability or degradation.

Key Points:

• RING-UIM E3 ligases bind and stabilize monoubiquitylated tankyrase.
• These ligases promote K11-linked diubiquitylation of tankyrase, opposing RNF146-mediated K48-linked polyubiquitylation and degradation.
• Tankyrase stabilization by RING-UIM ligases impacts downstream targets like Angiomotin, involved in cancer signaling.

Conclusions:

• Discovered a novel K11 ubiquitylation mechanism for tankyrase that counteracts K48-linked degradation.
• Identified multiple PAR-binding E3 ligases involved in regulating tankyrase ubiquitylation.
• These findings provide new insights into tankyrase regulation and suggest novel therapeutic strategies using tankyrase inhibitors in cancer treatment.