Title:Targeting Transcription Factor Binding to DNA by Competing with DNA Binders as an Approach for Controlling Gene Expression
Volume: 15
Issue: 14
Author(s): Mohamed Amine Bouhlel, Melanie Lambert and Marie-Helene David-Cordonnier
Affiliation:
Keywords:
Alkylating drugs, Competition, DNA binding, DNA ligands, Gene expression, Groove binders, Intercalators, Transcription
factors.
Abstract: Transcription factors are recognized as the master regulators of gene expression. Interestingly,
about 10% of the transcription factors described in mammals are up to date directly implicated
in a very large number of human diseases. With the exception of ligand-inducible nuclear receptors,
transcription factors have longtime been considered as “undruggable” targets for therapeutics. However,
the significant breakthroughs in their protein biochemistry and interactions with DNA at the
structural level, together with increasing needs for new targeted-approaches particularly in cancers,
has changed this postulate and opened the way for targeting transcription factors. Along with a better
knowledge of their specific DNA binding sequences by genome wide and high throughput sequencing assay, these informations
make possible the potent targeting of the transcription factors by three approaches dependently of their mechanism
of action. In this review, we discuss the different physicochemical interactions between the transcription factors and
the DNA helix, and the protein/protein interactions within a transcription factor complex and their impacts on the DNA
structure. In order to impair transcription factor activities, small molecules compounds can either act by direct interaction
on the transcription factor, or by blocking the protein/protein interactions in a transcription complex, or by competing with
the transcription factor itself and specifically targeting its cognate binding sequence. For this latter mode of transcription
targeting, we pay special attention to the DNA intercalating, alkylating or groove binders for transcription factor/DNA
binding modulation.
