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J. Biol. Chem., Vol. 277, Issue 21, 18489-18493, May 24, 2002
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From the Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Nonsense-mediated decay (NMD) is an RNA
surveillance pathway that degrades mRNAs containing premature
termination codons (PTC). T-cell receptor (TCR) and immunoglobulin (Ig)
transcripts, which are encoded by genes that very frequently acquire
PTCs during lymphoid ontogeny, are down-regulated much more
dramatically in response to PTCs than are other known transcripts.
Another feature unique to TCR, Ig, and a subset of other mRNAs is
that they are down-regulated in response to nonsense codons in the
nuclear fraction of cells. This is paradoxical, as the only well
recognized entity that recognizes nonsense codons is the cytoplasmic
translation apparatus. Therefore, we investigated whether translation
is responsible for this nuclear-associated mechanism. We found that the
down-regulation of TCR-
A Quality Control Pathway That Down-regulates Aberrant T-cell
Receptor (TCR) Transcripts by a Mechanism Requiring UPF2 and
Translation*
transcripts in response to nonsense codons
requires several features of translation, including an initiator ATG
and the ability to scan. We also found that optimal down-regulation
depends on a Kozak consensus sequence surrounding the initiator ATG and
that it can be initiated by an internal ribosome entry site,
neither of which has been demonstrated before for any other PTC-bearing mRNA. At least a portion of this down-regulatory response is
mediated by the NMD pathway as antisense hUPF2 transcripts increased
the levels of PTC-bearing TCR- transcripts in the nuclear
fraction of cells. We conclude that a hUPF2-dependent RNA
surveillance pathway with translation-like features operating in the
nuclear fraction of cells prevents the expression of potentially
deleterious truncated proteins encoded by non-productively rearranged
TCR genes.
*
This work was supported by National Institutes of Health
Grant GM 58595 and National Science Foundation Grant MCB-9808936.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Immunology,
Box 180, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-794-5526; Fax: 713-745-0846; E-mail: mwilkins@mail.mdanderson.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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