AI Article Synopsis
- Velcrin compounds can kill certain cancer cells by causing two proteins, PDE3A and SLFN12, to work together, but we don’t fully understand how this happens yet.
- SLFN12 targets and breaks down a specific type of RNA called tRNA(TAA), especially when treated with Velcrin.
- This breaking down of tRNA(TAA) by SLFN12 leads to a stop in making proteins in the cells, which may help trigger cell death, a process called apoptosis.
Article Abstract
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 tRNA(TAA). SLFN12 selectively digests tRNA(TAA), and velcrin treatment promotes the cleavage of tRNA(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNA(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNA(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNA(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.
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| http://dx.doi.org/10.1038/s41589-022-01170-9 | DOI Listing |
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