DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth

TY - JOUR

T1 - DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth

AU - Schleich, Sibylle

AU - Strassburger, Katrin

AU - Janiesch, Phillipp Christoph

AU - Koledachkina, Tatyana

AU - Miller, Katharine K

AU - Haneke, Katharina

AU - Cheng, Yong-Sheng

AU - Küchler, Katrin

AU - Stoecklin, Georg

AU - Duncan, Kent E

AU - Teleman, Aurelio A

N1 - UKE Publication of the Month August 2014 Sybille Schleich, Philipp Christoph Janiesch, Katharine K Miller and Katrin Küchler should all be affiliated with "Sonstige MitarbeiterInnen und Einrichtungen des ZMNH"

PY - 2014/8/14

Y1 - 2014/8/14

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Cells, Cultured

KW - Drosophila Proteins

KW - Drosophila melanogaster

KW - Eukaryotic Initiation Factors

KW - Gene Expression Regulation

KW - Open Reading Frames

KW - Protein Biosynthesis

KW - Signal Transduction

KW - translational control

KW - Organogenesis

U2 - 10.1038/nature13401

DO - 10.1038/nature13401

M3 - SCORING: Journal article

C2 - 25043021

VL - 512

SP - 208

EP - 212

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7513

ER -