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Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death

Sooncheol Lee1,2, Stephanie Hoyt1, Xiaoyun Wu1,3

  • 1Cancer Program, Broad Institute, Cambridge, MA, USA.

Nature Chemical Biology
|October 27, 2022
PubMed

Insights

Velcrin compounds kill cancer cells by forming a PDE3A-SLFN12 complex that degrades tRNALeu(TAA). This leads to protein synthesis inhibition and apoptosis, revealing a novel cancer cell death mechanism.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Velcrin compounds target cancer cells expressing phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12).
  • The precise mechanism by which the PDE3A-SLFN12 complex induces cancer cell death remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of cancer cell killing mediated by the PDE3A-SLFN12 complex.
  • To identify the physiological substrate of SLFN12 RNase and its role in velcrin-induced apoptosis.

Main Methods:

  • In vitro complex formation assays between PDE3A and SLFN12.
  • Analysis of tRNALeu(TAA) digestion by SLFN12.
  • Assessment of velcrin's effect on tRNA levels and protein synthesis in sensitive cancer cells.

Main Results:

  • The physiological substrate of SLFN12 RNase is identified as tRNALeu(TAA).
  • Velcrin treatment induces PDE3A-SLFN12 complex formation, promoting tRNALeu(TAA) cleavage.
  • Specific sequences in the variable loop and acceptor stem of tRNALeu(TAA) are crucial for its digestion.
  • Velcrin treatment downregulates tRNALeu(TAA), causes ribosome pausing at Leu-TTA codons, and globally inhibits protein synthesis.

Conclusions:

  • Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 is a key event in cancer cell killing.
  • The resulting global inhibition of protein synthesis represents a novel mechanism for initiating apoptosis in cancer cells.

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