Translation Control, Protein Biosynthesis & RNA Degradation

How do cells decide which messages to read, and when to destroy the script?

In Simple Terms

Every cell carries thousands of working copies of its genes, called messenger RNAs. These are the instructions a cell reads to build proteins, the molecules that do almost everything in biology. A cell cannot read every message at once, so it constantly chooses which instructions to translate, how fast, and which ones to recycle or throw away. We study how those choices are made. Getting them right lets a cell grow, respond to food, cope with stress and stay healthy; getting them wrong contributes to disease. We build methods that let us watch this decision making in real cells, message by message.

The Science

Our experimental core is Translation Complex Profile sequencing (TCP-seq) and its enhanced variant eTCP-seq, which fix and capture ribosomes and pre-initiation complexes across whole transcriptomes to reveal, at near single-nucleotide resolution, where the translation machinery sits during scanning, initiation, elongation and termination. We pair this with Stochastic Translation Efficiency (STE) modelling to separate genuine regulation from the noise inherent in per-cell protein synthesis, and with INDEGRA to read RNA integrity and degradation kinetics directly from the same sequencing data. Together these let us connect the moment-to-moment behaviour of ribosomes to the stability and turnover of the messages they read, and to quantify how quickly cells reshape their proteome when conditions change.

A ribosome moving along a messenger RNA, with the footprint density trace the group measures above itribosome footprintsAUGstop5′UTRcoding sequence3′UTRpoly(A)EPAfootprints show which messages are being read

Key Publications

Dynamics of ribosome scanning and recycling revealed by translation complex profiling

Archer, Stuart K; Shirokikh, Nikolay E; Beilharz, Traude H; Preiss, Thomas

Nature 535(7613), 570-574

Translation complex profile sequencing to study the in vivo dynamics of mRNA–ribosome interactions during translation initiation, elongation and termination

Shirokikh, Nikolay E; Archer, Stuart K; Beilharz, Traude H; Powell, David; Preiss, Thomas

Nature protocols 12(4), 697-731

Comprehensive translational profiling and STE AI uncover rapid control of protein biosynthesis during cell stress

Horvath, Attila; Janapala, Yoshika; Woodward, Katrina; Mahmud, Shafi; Cleynen, Alice; Gardiner, Elizabeth E; Hannan, Ross D; Eyras, Eduardo; Preiss, Thomas; Shirokikh, Nikolay E

Nucleic Acids Research 52(13), 7925-7946

High-Accuracy RNA Integrity Definition for Unbiased Transcriptome Comparisons with INDEGRA

A Cleynen, A Ravindran, A Sethi, B Kumar, T Javaid, S Mahmud, ...

bioRxiv 2024.12.12.627949

Preprint

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