TY - JOUR
T1 - C→U editing of neurofibromatosis 1 mrna occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRna-editing enzyme
AU - Mukhopadhyay, Debnath
AU - Anant, Shrikant
AU - Lee, Robert M.
AU - Kennedy, Susan
AU - Viskochil, David
AU - Davidson, Nicholas O.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants HL-38180 and DK-56260 and NIH Digestive Disease Research Core Center grant DK-52574 (all to N.O.D.). The authors acknowledge the generous assistance of Drs. David N. Louis (Massachusetts General Hospital, Boston) and Priscilla Short (University of Chicago Hospitals) for their provision of samples for these analyses. In addition, the authors acknowledge their colleagues, Valerie Blanc, Libby Newberry, and Jeffrey Henderson, for their valuable insights and discussion.
PY - 2002
Y1 - 2002
N2 - C→U RNA editing of neurofibromatosis 1 (NF1) mRNA changes an arginine (CGA) to a UGA translational stop codon, predicted to result in translational termination of the edited mRNA. Previous studies demonstrated varying degrees of C→U RNA editing in peripheral nerve-sheath tumor samples (PNSTs) from patients with NF1, but the basis for this heterogeneity was unexplained. In addition, the role, if any, of apobec-1, the catalytic deaminase that mediates C→U editing of mammalian apolipoprotein B (apoB) RNA, was unresolved. We have examined these questions in PNSTs from patients with NF1 and demonstrate that a subset (8/34) manifest C→U editing of RNA. Two distinguishing characteristics were found in the PNSTs that demonstrated editing of NF1 RNA. First, these tumors express apobec-1 mRNA, the first demonstration, in humans, of its expression beyond the luminal gastrointestinal tract. Second, PNSTs with C→U editing of RNA manifest increased proportions of an alternatively spliced exon, 23A, downstream of the edited base. C→U editing of RNA in these PNSTs was observed preferentially in transcripts containing exon 23A. These findings were complemented by in vitro studies using synthetic RNA templates incubated in the presence of recombinant apobec-1, which again confirmed preferential editing of transcripts containing exon 23A. Finally, adenovirus-mediated transfection of HepG2 cells revealed induction of editing of apoB RNA, along with preferential editing of NF1 transcripts containing exon 23A. Taken together, the data support the hypothesis that C→U RNA editing of the NF1 transcript occurs both in a subset of PNSTs and in an alternatively spliced form containing a downstream exon, presumably an optimal configuration for enzymatic deamination by apobec-1.
AB - C→U RNA editing of neurofibromatosis 1 (NF1) mRNA changes an arginine (CGA) to a UGA translational stop codon, predicted to result in translational termination of the edited mRNA. Previous studies demonstrated varying degrees of C→U RNA editing in peripheral nerve-sheath tumor samples (PNSTs) from patients with NF1, but the basis for this heterogeneity was unexplained. In addition, the role, if any, of apobec-1, the catalytic deaminase that mediates C→U editing of mammalian apolipoprotein B (apoB) RNA, was unresolved. We have examined these questions in PNSTs from patients with NF1 and demonstrate that a subset (8/34) manifest C→U editing of RNA. Two distinguishing characteristics were found in the PNSTs that demonstrated editing of NF1 RNA. First, these tumors express apobec-1 mRNA, the first demonstration, in humans, of its expression beyond the luminal gastrointestinal tract. Second, PNSTs with C→U editing of RNA manifest increased proportions of an alternatively spliced exon, 23A, downstream of the edited base. C→U editing of RNA in these PNSTs was observed preferentially in transcripts containing exon 23A. These findings were complemented by in vitro studies using synthetic RNA templates incubated in the presence of recombinant apobec-1, which again confirmed preferential editing of transcripts containing exon 23A. Finally, adenovirus-mediated transfection of HepG2 cells revealed induction of editing of apoB RNA, along with preferential editing of NF1 transcripts containing exon 23A. Taken together, the data support the hypothesis that C→U RNA editing of the NF1 transcript occurs both in a subset of PNSTs and in an alternatively spliced form containing a downstream exon, presumably an optimal configuration for enzymatic deamination by apobec-1.
UR - http://www.scopus.com/inward/record.url?scp=0036006807&partnerID=8YFLogxK
U2 - 10.1086/337952
DO - 10.1086/337952
M3 - Article
C2 - 11727199
AN - SCOPUS:0036006807
SN - 0002-9297
VL - 70
SP - 38
EP - 50
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -