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Molecular and Cellular Biology, September 1998, p. 5272-5283, Vol. 18, No. 9
Department of Cancer Genetics, Roswell Park
Cancer Institute, New York State Department of Health, Buffalo, New
York 14263
Received 19 November 1997/Returned for modification 21 January
1998/Accepted 1 June 1998
Mammalian cells have established mechanisms to reduce the abundance
of mRNAs that harbor a nonsense codon and prematurely terminate
translation. In the case of the human triosephosphate isomerase (TPI
gene), nonsense codons located less than 50 to 55 bp upstream of intron
6, the 3'-most intron, fail to mediate mRNA decay. With the aim of
understanding the feature(s) of TPI intron 6 that confer function in
positioning the boundary between nonsense codons that do and do not
mediate decay, the effects of deleting or duplicating introns have been
assessed. The results demonstrate that TPI intron 6 functions to
position the boundary because it is the 3'-most intron. Since decay
takes place after pre-mRNA splicing, it is conceivable that removal of
the 3'-most intron from pre-mRNA "marks" the 3'-most exon-exon
junction of product mRNA so that only nonsense codons located more than
50 to 55 nucleotides upstream of the "mark" mediate mRNA decay.
Decay may be elicited by the failure of translating ribosomes to
translate sufficiently close to the mark or, more likely, the scanning
or looping out of some component(s) of the translation termination complex to the mark. In support of scanning, a nonsense codon does not
elicit decay if some of the introns that normally reside downstream of
the nonsense codon are deleted so the nonsense codon is located (i) too
far away from a downstream intron, suggesting that all exon-exon
junctions may be marked, and (ii) too far away from a downstream
failsafe sequence that appears to function on behalf of intron 6, i.e.,
when intron 6 fails to leave a mark. Notably, the proposed scanning
complex may have a greater unwinding capability than the complex that
scans for a translation initiation codon since a hairpin structure
strong enough to block translation initiation when inserted into the 5'
untranslated region does not block nonsense-mediated decay when
inserted into exon 6 between a nonsense codon residing in exon 6 and
intron 6.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
At Least One Intron Is Required for the
Nonsense-Mediated Decay of Triosephosphate Isomerase mRNA: a Possible
Link between Nuclear Splicing and Cytoplasmic Translation


*
Corresponding author. Mailing address: Department of
Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-3325. Fax: (716) 845-8449. E-mail:
Maquat{at}sc3101.med.buffalo.edu.
Present address: Millennium Pharmaceutical, Inc., Cambridge, MA
02139.
Present address: Albert Einstein College of Medicine, Department
of Molecular Pharmacology, Bronx, NY 10461.
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