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Garg, D. ; Beribisky, A.V. ; Ponterini, G.* ; Ligabue, A.* ; Marverti, G.* ; Martello, A.* ; Costi, M.P.* ; Sattler, M. ; Wade, R.C.*

Translational repression of thymidylate synthase by targeting its mRNA.

Nucleic Acids Res. 41, 4159-4170 (2013)
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Resistance to drugs targeting human thymidylate synthase (TS) poses a major challenge in the field of anti-cancer therapeutics. Overexpression of the TS protein has been implicated as one of the factors leading to the development of resistance. Therefore, repressing translation by targeting the TS mRNA could help to overcome this problem. In this study, we report that the compound Hoechst 33258 (HT) can reduce cellular TS protein levels without altering TS mRNA levels, suggesting that it modulates TS expression at the translation level. We have combined nuclear magnetic resonance, UV-visible and fluorescence spectroscopy methods with docking and molecular dynamics simulations to study the interaction of HT with a region in the TS mRNA. The interaction predominantly involves intercalation of HT at a CC mismatch in the region near the translational initiation site. Our results support the use of HT-like compounds to guide the design of therapeutic agents targeting TS mRNA.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Electric Linear Dichroism ; Molecular-dynamics ; Aqueous-solutions ; Nmr-spectroscopy ; Binding Modes ; Hoechst 33258 ; Dna ; Site ; Drugs ; Water
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Journal Nucleic Acids Research
Quellenangaben Volume: 41, Issue: 7, Pages: 4159-4170 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
PubMed ID 23423353
DOI 10.1093/nar/gkt098
WOS ID WOS:000318167900033
Scopus ID 84876538176
Erfassungsdatum 2013-05-31
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