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Translational repression of thymidylate synthase by targeting its mRNA

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 m...

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Bibliographic Details
Main Authors: Garg, Divita (Author) , Beribisky, Alexander V. (Author) , Ponterini, Glauco (Author) , Ligabue, Alessio (Author) , Marverti, Gaetano (Author) , Martello, Andrea (Author) , Costi, M. Paola (Author) , Sattler, Michael (Author) , Wade, Rebecca C. (Author)
Format: Article (Journal)
Language:English
Published: 18 February 2013
In: Nucleic acids research
Year: 2013, Volume: 41, Issue: 7, Pages: 4159-4170
ISSN:1362-4962
DOI:10.1093/nar/gkt098
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/nar/gkt098
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Author Notes:Divita Garg, Alexander V. Beribisky, Glauco Ponterini, Alessio Ligabue, Gaetano Marverti, Andrea Martello, M. Paola Costi, Michael Sattler and Rebecca C. Wade
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Summary: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.
Item Description:Gesehen am 27.01.2020
Physical Description:Online Resource
ISSN:1362-4962
DOI:10.1093/nar/gkt098

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