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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • ADP-ribosylation is a key posttranslational modification regulating cellular signaling pathways.
  • Tankyrases, members of the ARTD superfamily, possess unique domains (sterile alpha motif, ankyrin repeats) and regulate critical cellular functions.
  • Tankyrase activity influences telomere homeostasis, Wnt/β-catenin signaling, glucose metabolism, and cell cycle progression.

Purpose of the Study:

  • To explore the role of Tankyrases in cellular signaling.
  • To investigate the mechanism of Tankyrase-mediated protein regulation.
  • To highlight the therapeutic potential of novel Tankyrase inhibitors.

Main Methods:

  • Studied ADP-ribosylation as a posttranslational modification.
  • Investigated the domain organization and function of Tankyrases.
  • Examined the role of RNF146 in ubiquitination and proteasomal degradation of Tankyrase substrates.
  • Described small molecule inhibitors targeting the ARTD catalytic domain of Tankyrases.

Main Results:

  • Tankyrases regulate protein stability and interactions via poly (ADP-ribosyl)ation.
  • Modified proteins are targeted for degradation by the E3 ubiquitin ligase RNF146 and the 26S proteasome.
  • Potent and selective small molecule inhibitors of Tankyrases have been developed.
  • These inhibitors compete with NAD+ for binding to the ARTD catalytic domain.

Conclusions:

  • Tankyrase activity is a critical regulator of multiple cellular processes.
  • The developed small molecule inhibitors are promising lead compounds.
  • These inhibitors offer potential for proof-of-concept studies in cancer and Tankyrase-related diseases.