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Targeting a Regulatory Element in Human Thymidylate Synthase mRNA
Author(s) -
Brunn Nicholas D.,
Garcia Sega Emily,
Kao Melody B.,
Hermann Thomas
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201200603
Subject(s) - thymidylate synthase , messenger rna , translation (biology) , biology , eukaryotic translation , microbiology and biotechnology , rna , translational regulation , protein biosynthesis , biochemistry , chemistry , gene , genetics , cancer , fluorouracil
Thymidylate synthase (TS) is a key enzyme in the biosynthesis of thymidine. The use of TS inhibitors in cancer chemotherapy suffers from resistance development in tumors through upregulation of TS expression. Autoregulatory translation control has been implicated with TS overexpression. TS binding at its own mRNA, which leads to sequestration of the start codon, is abolished when the enzyme forms an inhibitor complex, thereby relieving translation suppression. We have used the protein‐binding site from the TS mRNA in the context of a bicistronic expression system to validate targeting the regulatory motif with stabilizing ligands that prevent ribosomal initiation. Stabilization of the RNA by mutations, which were studied as surrogates of ligand binding, suppresses translation of the TS protein. Compounds that stabilize the TS‐binding RNA motif and thereby inhibit ribosomal initiation might be used in combination with existing TS enzyme‐targeting drugs to overcome resistance development during chemotherapy.