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Abstract
The non-canonical initiation factors DENR and MCTS1 have been linked to cancer and autism. We recently showed in Drosophila that DENR and MCTS1 regulate translation re-initiation on transcripts containing upstream Open Reading Frames (uORFs) with strong Kozak sequences (stuORFs). Due to the medical relevance of DENR and MCTS1, it is worthwhile identifying the transcripts in human cells that depend on DENR and MCTS1 for their translation. We show here that in humans, as in Drosophila, transcripts with short stuORFs require DENR and MCTS1 for their optimal expression. In contrast to Drosophila, however, the dependence on stuORF length in human cells is very strong, so that only transcripts with very short stuORFs coding for 1 amino acid are dependent on DENR and MCTS1. This identifies circa 100 genes as putative DENR and MCTS1 translational targets. These genes are enriched for neuronal genes and G protein-coupled receptors. The identification of DENR and MCTS1 target transcripts will serve as a basis for future studies aimed at understanding the mechanistic involvement of DENR and MCTS1 in cancer and autism.
Highlights
DENR and MCTS1 are two non-canonical initiation factors that form a complex[1]
We previously showed in Drosophila that stuORF containing transcripts are DENRMCTS1 targets and that this class of genes is enriched for transcription factors, cell membrane receptors, and genes involved in neuron morphogenesis[6]
Knockdown of either DENR or MCTS1 did not reduce expression of the control reporter, but reduced expression of the stuORF reporter (Fig. 1A)
Summary
DENR and MCTS1 are two non-canonical initiation factors that form a complex[1]. MCTS1 was identified by the Gartenhaus lab as an oncogene that is genomically amplified in T-cell leukemias[2]. The Shatsky and Pestova groups have shown that DENR and MCTS1, or the structurally and functionally related protein Ligatin/eIF2D, have biochemical activities in vitro that are likely relevant for translation reinitiation they can recycle post-termination ribosomal complexes and they can recruit Met-tRNAiMet to the 40S ribosomal subunit in a non-canonical, eIF2-independent manner on viral mRNAs9, 10. In this study we report the identification of very short stuORF-containing transcripts as targets for DENRMCTS1 in human cells, and find that this class of transcripts is enriched for neuronal genes
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