Author: Lee, Sooncheol; Hoyt, Stephanie; Wu, Xiaoyun; Garvie, Colin; McGaunn, Joseph; Shekhar, Mrinal; Totzl, Marcus; Rees, Matthew G.; Cherniack, Andrew D.; Meyerson, Matthew; Greulich, Heidi
Description: Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
Subject headings: RNA; Transfer; Leu; Cell Line; Tumor; Cell Death; Apoptosis; Protein Biosynthesis; Neoplasms; Velcrin; Cancer
Publication year: 2023
Journal or book title: Nature Chemical Biology
Volume: 19
Issue: 3
Pages: 301-310
Find the full text: https://www.nature.com/articles/s41589-022-01170-9
Find more like this one (cited by): https://scholar.google.com/scholar?cites=6528112616305359848&as_sdt=1000005&sciodt=0,16&hl=en
Serial number: 3912