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Ribosome decoding memory directs translational re-coding of codon repeats

ABSTRACT: During mRNA translation, ribosome dynamics at individual codons critically shape the quality and quantity of protein products. Long runs of consecutive codons are generally thought to impede elongation by depleting cognate tRNAs. However, in Huntington’s disease, ribosomes translate hundreds of consecutive CAG codons without catastrophic stalling. Here, we systematically profile ribosome behavior across repeats of all 20 amino acids encoded in the human genome. For proline and lysine repeats – commonly considered difficult to decode – we find that ribosomes accelerate after an initial phase of slow decoding, a phenomenon we term adaptive decoding. Remarkably, codon-specific decoding memory enables iterative translation of arginine repeats, generating internally expanded protein products. In contrast, acidic amino acid repeats trigger ribosomal bypassing and produce internally truncated proteins. Contrary to prevailing assumptions, decoding inertia acquired during repeat translation constraints frameshifting. Disrupting the decoding memory of CAG repeats by inserting proline codons is beneficial in reducing polyglutamine synthesis and aggregation. These findings uncover an adaptive dimension of ribosome decoding that contributes to the synthesis of physiological and pathological amino acid repeats.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320341 | GEO | 2026/04/20

REPOSITORIES: GEO

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