DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders

Ramona Weber (), Leon Kleemann, Insa Hirschberg, Min-Yi Chung, Eugene Valkov and Cátia Igreja ()
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Ramona Weber: Department of Biochemistry, Max Planck Institute for Developmental Biology
Leon Kleemann: Department of Biochemistry, Max Planck Institute for Developmental Biology
Insa Hirschberg: Friedrich Miescher Laboratory of the Max Planck Society
Min-Yi Chung: Department of Biochemistry, Max Planck Institute for Developmental Biology
Eugene Valkov: Department of Biochemistry, Max Planck Institute for Developmental Biology
Cátia Igreja: Department of Biochemistry, Max Planck Institute for Developmental Biology

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here, we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is required for translation initiation on select transcripts. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated translation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates main CDS, but not uORF, translation suggesting a role for DAP5 in translation re-initiation. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.

Date: 2022
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DOI: 10.1038/s41467-022-35019-5

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