生命科学联合中心学术报告
题目：When Cells become dyslexic - Connecting RNA and protein quality control
报告人：Sebastian Andreas Leidel, Ph.D.
Max Planck Research Group Leader at the Max Planck Institute for Molecular Biomedicine
时间：2017-5-4（周四），14:30pm-15:30pm
地点：北京大学金光生命科学大楼101报告厅
联系人：伊成器  北大-清华生命科学联合中心
Transfer RNAs (tRNA) carry a plethora of chemical modifications at many individual nucleotides. Modifications in the tRNA anticodon form a part of the core translational apparatus, and their loss leads to cellular dysfunction and neurodevelopmental disorders through unknown mechanisms. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs slows translation at their cognate codons in yeast, nematodes, and the developing mouse brain. Surprisingly, codon-specific ribosome pauses elicit the aggregation of many essential proteins, profoundly impairing the ability of cells to balance protein homeostasis and to clear stress-induced protein aggregates. The proteotoxic stress triggered by ablating U34 modifications in murine cortical stem cells switches cell fate decisions in the developing cortex, leading to severe microcephaly. Remarkably, the restoration of codon-specific translation speed by tRNA overexpression is sufficient to reduce the cellular burden of protein aggregates, concomitantly relieving proteotoxic stress and restoring cellular fitness. Our findings reveal a hitherto unappreciated role of tRNA anticodon modifications in maintaining proteome integrity and suggest that protein homeostasis breakdown underlies the neurodevelopmental pathologies linked to aberrant U34 modification.
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