Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs.

ABSTRACT: mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5' untranslated regions (UTRs) including alternative isoforms and identify sequences that mediate 200-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3-6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-

SUBMITTER: Lewis CJT 

PROVIDER: S-EPMC11780321 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature