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Regulation of the mRNA reading frame
Author(s) -
Dunham Christine M.,
Sunita S.,
Dunkle Jack,
Maehigashi Tatsuya
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.113.1
Subject(s) - translational frameshift , frameshift mutation , ribosome , messenger rna , translation (biology) , transfer rna , open reading frame , biology , 30s , protein biosynthesis , reading frame , upstream open reading frame , genetics , microbiology and biotechnology , computational biology , rna , gene , peptide sequence , exon
The ribosome is a massive, universally conserved macromolecular machine responsible for all cellular protein synthesis. The ribosome selects correct tRNAs to decode the mRNA, facilitates peptide bond formation, and then moves the tRNAs through its three functionally distinct tRNA binding sites in a dynamic and exquisitely orchestrated manner. Accurate maintenance of the universal mRNA three‐nucleotide code (or “reading frame”) is critical for correct protein expression but the molecular details of how this is controlled, or deviated from in a programmed manner, are not well understood. The absolute requirement for the precise correlation between the mRNA frame and the correct protein sequence expressed underlies an important fundamental but unanswered question in molecular biology: what regulates the mRNA reading frame? To address this question, we study two examples of defined biological mechanisms that subvert the three‐nucleotide mRNA reading frame and undergo high levels of frameshifting, i.e. movement to a noncanonical reading of the mRNA template. Here we describe two ribosomal frameshift events, a +1 ( i.e. four rather than the normal three mRNA nucleotide) reading of the mRNA template by frameshift suppressor tRNAs and a ‐1 ( i.e. two mRNA nucleotide) reading of the mRNA template induced by complex mRNA tertiary structures proximal to the surface of the ribosome. Our biochemical and structural results reveal that tRNA distortion and conformational changes of the small ribosomal subunit are induced by frameshift‐prone tRNAs and mRNAs. We propose nonproductive EF‐G interaction with the ribosome results in a pausing of EF‐G‐mediated translocation of the mRNA‐tRNA pair allowing for the shift in a new mRNA frame. Support or Funding Information NIH R01GM093278; Pew Biomedical Trusts