【Date】 Apr. 9 (Mon), 2018 16:00～17:00
【Venue】Conference room, 1st floor,
Institute of Molecular Embryology and Genetics (IMEG),
Kumamoto University
【Title】Genomic, molecular, and structural basis for mRNA-selective translation inhibitor Rocaglamide A
【Speaker】Shintaro Iwasaki Ph.D.
Chief Scientist, RIKEN
Associate Professor
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo
【Abstract】
A novel class of translation inhibitor Rocaglamide A (RocA) or its derivative has been isolated from Meliaceae family plant Aglaia and showed promise as anti-cancer therapies. RocA targets eukaryotic translation initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, and its mRNA selectivity is proposed to reflect highly structured 5′ UTRs that require eIF4A-mediated unwinding strongly. Here, by ribosome profiling and other deep sequencing based techniques, we show that secondary structure in 5′ UTRs is only a minor determinant for RocA selectivity and RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing gene expression on transcripts bearing the RocA•eIF4A target sequence.
Moreover, we revealed the resistance and the structure of RocA. Although the biosynthesis of natural translation inhibitor in Aglaia raises the question of molecular basis behind its resistance, the detailed mechanism has been unclear. We assembled Aglaia transcriptome de novo and found unique mutations in eIF4A to evade RocA-dependent translation inhibition. Furthermore, we determined the crystal structure of the human eIF4A1•ATP analog•RocA•polypurine RNA complex. RocA is inserted between the sharply-bent two consecutive purines and the Aglaia-specific mutation residues. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide the first example of a drug stabilizing sequence-selective RNA-protein
※このセミナーは日本語にて開催されます。
【連絡先】染色体制御分野 石黒 啓一郎（内線 6606）
