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Title: Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA

Abstract

A sequence around the start codon of the mRNA of human thymidylate synthase (TS) folds into a secondary-structure motif in which the initiation site is sequestered in a metastable hairpin. Binding of the protein to its own mRNA at the hairpin prevents the production of TS through a translation-repression feedback mechanism. Stabilization of the mRNA hairpin by other ligands has been proposed as a strategy to reduce TS levels in anticancer therapy. Rapidly proliferating cells require high TS activity to maintain the production of thymidine as a building block for DNA synthesis. The crystal structure of a model oligonucleotide (TS1) that represents the TS-binding site of the mRNA has been determined. While fluorescence studies showed that the TS1 RNA preferentially adopts a hairpin structure in solution, even at high RNA concentrations, an asymmetric dimer of two hybridized TS1 strands was obtained in the crystal. The TS1 dimer contains an unusual S-turn motif that also occurs in the 'off' state of the human ribosomal decoding site RNA.

Authors:
; ;  [1]
  1. (UCSD)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1025637
Resource Type:
Journal Article
Journal Name:
Acta Crystallogr. D
Additional Journal Information:
Journal Volume: 67; Journal Issue: (2) ; 02, 2011; Journal ID: ISSN 0907-4449
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CODONS; CRYSTAL STRUCTURE; DIMERS; DNA; FEEDBACK; FLUORESCENCE; OLIGONUCLEOTIDES; PRODUCTION; PROTEINS; RNA; STABILIZATION; SYNTHESIS; THERAPY; THYMIDINE

Citation Formats

Dibrov, Sergey, McLean, Jaime, and Hermann, Thomas. Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA. United States: N. p., 2011. Web. doi:10.1107/S0907444910050900.
Dibrov, Sergey, McLean, Jaime, & Hermann, Thomas. Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA. United States. doi:10.1107/S0907444910050900.
Dibrov, Sergey, McLean, Jaime, and Hermann, Thomas. Tue . "Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA". United States. doi:10.1107/S0907444910050900.
@article{osti_1025637,
title = {Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA},
author = {Dibrov, Sergey and McLean, Jaime and Hermann, Thomas},
abstractNote = {A sequence around the start codon of the mRNA of human thymidylate synthase (TS) folds into a secondary-structure motif in which the initiation site is sequestered in a metastable hairpin. Binding of the protein to its own mRNA at the hairpin prevents the production of TS through a translation-repression feedback mechanism. Stabilization of the mRNA hairpin by other ligands has been proposed as a strategy to reduce TS levels in anticancer therapy. Rapidly proliferating cells require high TS activity to maintain the production of thymidine as a building block for DNA synthesis. The crystal structure of a model oligonucleotide (TS1) that represents the TS-binding site of the mRNA has been determined. While fluorescence studies showed that the TS1 RNA preferentially adopts a hairpin structure in solution, even at high RNA concentrations, an asymmetric dimer of two hybridized TS1 strands was obtained in the crystal. The TS1 dimer contains an unusual S-turn motif that also occurs in the 'off' state of the human ribosomal decoding site RNA.},
doi = {10.1107/S0907444910050900},
journal = {Acta Crystallogr. D},
issn = {0907-4449},
number = (2) ; 02, 2011,
volume = 67,
place = {United States},
year = {2011},
month = {9}
}