Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) are homologous proteins implicated in various pathways and diseases, notably cancer.
• TNKS1/2 possess an ankyrin (ANK) domain that binds the Tankyrase Binding Motif (TBM) in diverse substrates.
• A key function of tankyrases is regulating protein stability through PARylation-dependent ubiquitination (PARdU), though other roles are less understood.

Purpose of the Study:

• To review diverse tankyrase substrates and analyze the biological consequences of their interaction with TNKS1/2.
• To examine canonical and non-canonical Tankyrase Binding Motifs (TBMs).
• To focus on the role of TNKS1/2 in various tumor contexts and evaluate current and novel inhibitor strategies.

Main Methods:

• Literature review and synthesis of existing data on tankyrase function, substrates, and inhibitors.
• Analysis of biological pathways involving TNKS1/2 and their substrates.
• Evaluation of current therapeutic strategies targeting tankyrases.

Main Results:

• Tankyrases play multifaceted roles beyond PARdU, impacting various cellular processes.
• Understanding both canonical and non-canonical TBMs is crucial for comprehending substrate specificity.
• Current TNKS inhibitors target the catalytic PARP domain, but novel strategies targeting the ANK domain are emerging.

Conclusions:

• Further research into tankyrase biology is essential for a comprehensive understanding of these PARP family members.
• Developing inhibitors targeting the ankyrin domain may offer improved therapeutic and safety profiles.
• Elucidating tankyrase functions can lead to more effective cancer treatments.