Aven recognition of RNA G-quadruplexes regulates translation of the mixed lineage leukemia protooncogenes.
G-quadruplexes (G4) are extremely stable secondary structures forming stacks of guanine tetrads. DNA G4 structures have been extensively studied, however, less is known about G4 motifs in mRNAs, especially in their coding sequences. Herein, we show that Aven stimulates the mRNA translation of the mixed lineage leukemia (MLL) proto-oncogene in an arginine methylation-dependent manner. The Aven RGG/RG motif bound G4 structures within the coding regions of the MLL1 and MLL4 mRNAs increasing their polysomal association and translation, resulting in the induction of transcription of leukemic genes. The DHX36 RNA helicase associated with the Aven complex and was required for optimal translation of G4 mRNAs. Depletion of Aven led to a decrease in synthesis of MLL1 and MLL4 proteins resulting in reduced proliferation of leukemic cells. These findings identify an Aven-centered complex that stimulates the translation of G4 harboring mRNAs, thereby promoting survival of leukemic cells.
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Palaniraja
P
Thandapani
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Jingwen
J
Song
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Valentina
V
Gandin
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Yutian
Y
Cai
Département de Biochimie, Université de Sherbrooke, Sherbrooke, Canada.
Samuel G
SG
Rouleau
Département de Biochimie, Université de Sherbrooke, Sherbrooke, Canada.
Jean-Michel
JM
Garant
Département d'Anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Pavillon de Recherche Appliquée au Cancer, Université de Sherbrooke, Sherbrooke, Canada.
Francois-Michel
FM
Boisvert
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Zhenbao
Z
Yu
Département de Biochimie, Université de Sherbrooke, Sherbrooke, Canada.
Jean-Pierre
JP
Perreault
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Ivan
I
Topisirovic
Terry Fox Molecular Oncology Group, Segal Cancer Center, Jewish General Hospital, Montréal, Canada.
Stéphane
S
Richard
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D054856:G-Quadruplexes; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D014176:Protein Biosynthesis; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism*
C412506:AVEN protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C530816:MLL4 protein, human; C466988:DHX36 protein, human; D053487:DEAD-box RNA Helicases
G-quadruplex; PRMT1; RNA-binding protein; arginine methylation; biochemistry; cell biology; human; mouse; translation