title: DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth.
abstract: During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process. Re-initiation is thought to involve the same factors as standard initiation. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth.
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Schleich
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Strassburger
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Philipp Christoph
authors.initials: PC
authors.lastname: Janiesch
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Koledachkina
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Katharine K
authors.initials: KK
authors.lastname: Miller
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haneke
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kuechler
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Stoecklin
authors.affiliation: Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Duncan
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000254:growth & development; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D016366:Open Reading Frames; D014176:Protein Biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C000591239:DENR protein, Drosophila; D029721:Drosophila Proteins; D039642:Eukaryotic Initiation Factors; C000591240:Mct1 protein, Drosophila