When cells become dyslexic – Connecting RNA and protein quality control – Sociedad de Bioquímica y Biología Molecular de Chile

Título: When cells become dyslexic – Connecting RNA and protein quality control
Expositor: Dr. Sebastian Leidel, Max Planck Institute for Molecular Biomedicine
Lugar: auditorio Alberto Donoso A (Facultad de Medicina, Escuela de posgrado, segundo piso).
Horario: Miércoles 22 de marzo a las 13:00 hrs.

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.