| Autor: |
Zhu X; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Cruz VE; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhang H; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA., Erzberger JP; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Mendell JT; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. |
| Abstrakt: |
The CCR4-NOT complex is a major regulator of eukaryotic messenger RNA (mRNA) stability. Slow decoding during translation promotes association of CCR4-NOT with ribosomes, accelerating mRNA degradation. We applied selective ribosome profiling to further investigate the determinants of CCR4-NOT recruitment to ribosomes in mammalian cells. This revealed that specific arginine codons in the P-site are strong signals for ribosomal recruitment of human CNOT3, a CCR4-NOT subunit. Cryo-electron microscopy and transfer RNA (tRNA) mutagenesis demonstrated that the D-arms of select arginine tRNAs interact with CNOT3 and promote its recruitment whereas other tRNA D-arms sterically clash with CNOT3. These effects link codon content to mRNA stability. Thus, in addition to their canonical decoding function, tRNAs directly engage regulatory complexes during translation, a mechanism we term P-site tRNA-mediated mRNA decay. |
