Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B Pre-mRNA Inhibits RNA Editing in Glioblastoma.
RNA editing is a cellular process that precisely alters nucleotide sequences, thus regulating gene expression and generating protein diversity. Over 60% of human transcripts undergo adenosine to inosine RNA editing, and editing is required for normal development and proper neuronal function of animals. Editing of one adenosine in the transcript encoding the glutamate receptor subunit B, glutamate receptor ionotropic AMPA 2 (GRIA2), modifies a codon, replacing the genomically encoded glutamine (Q) with arginine (R); thus this editing site is referred to as the Q/R site. Editing at the Q/R site ofGRIA2is essential, and reduced editing ofGRIA2transcripts has been observed in patients suffering from glioblastoma. In glioblastoma, incorporation of unedited GRIA2 subunits leads to a calcium-permeable glutamate receptor, which can promote cell migration and tumor invasion. In this study, we identify adenosine deaminase that acts on RNA 3 (ADAR3) as an important regulator of Q/R site editing, investigate its mode of action, and detect elevated ADAR3 expression in glioblastoma tumors compared with adjacent brain tissue. Overexpression of ADAR3 in astrocyte and astrocytoma cell lines inhibits RNA editing at the Q/R site ofGRIA2Furthermore, the double-stranded RNA binding domains of ADAR3 are required for repression of RNA editing. As the Q/R site ofGRIA2is specifically edited by ADAR2, we suggest that ADAR3 directly competes with ADAR2 for binding toGRIA2transcript, inhibiting RNA editing, as evidenced by the direct binding of ADAR3 to theGRIA2pre-mRNA. Finally, we provide evidence that both ADAR2 and ADAR3 expression contributes to the relative level ofGRIA2editing in tumors from patients suffering from glioblastoma.
From the Department of Biology and.
Eimile
E
Oakes
Medical Sciences Program, Indiana University, Bloomington, Indiana 47405 and.
Ashley
A
Anderson
Department of Neurological Surgery, Goodman Campbell Brain and Spine, Indianapolis, Indiana 46202.
Aaron
A
Cohen-Gadol
Medical Sciences Program, Indiana University, Bloomington, Indiana 47405 and hahundle@indiana.edu.
Heather A
HA
Hundley
D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D017393:RNA Editing / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*
D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D018698:Glutamic Acid; C548482:ADA protein, human; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; C104722:glutamate receptor ionotropic, AMPA 2
ADAR; ADAR3; GRIA2; RNA editing; adenosine deaminase; cancer; double-stranded RNA (dsRNA); glioblastoma; glutamate receptor; inosine