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Transcription factors as targets for DNA-interacting drugs
Marek Gniazdowski1, William A Denny, Stephanie M Nelson
1Department of Medicinal Chemistry, Institute of Physiology and Biochemistry, Medical University of Lódz, Poland. magn@csk.am.lodz.pl
Abstract:
Gene expression, both tissue specific or inducible, is controlled at the level of transcription by various transcription factors interacting with specific sequences of DNA. Anticancer drugs and other potential therapeutic agents alter interactions of regulatory proteins with DNA by a variety of different mechanisms. The main ones, considered in the review, are: i) competition for the transcription factor DNA binding sequences by drugs that interact non-covalently with DNA (e.g. anthracyclines, acridines, actinomycin D, pyrrole antibiotics and their polyamide derivatives); ii) covalent modifications of DNA by alkylating agents (e.g. nitrogen mustards, cisplatin) that prevent transcription factors from recognizing their specific sequences, or that result in multiple "unnatural" binding sites in DNA which hijack the transcription factors, thus decreasing their availability in the nucleus; iii) competition with binding sites on the transcription factors by synthetic oligonucleotides or peptide nucleic acids in an antigene strategy. The latter compounds may also compete for binding sites on regulatory proteins, acting as decoys to lower their active concentration in the cell. In this review, we have summarized recent advances which have been made towards understanding the above mechanisms by which small molecules interfere with the function of transcription factors.
Insights
Small molecules, including anticancer drugs, can disrupt gene transcription by interfering with transcription factors. These agents use various mechanisms, such as DNA binding competition or covalent modification, to alter gene expression regulation.
Area of Science:
- Molecular Biology
- Pharmacology
- Genetics
Background:
- Gene expression is regulated by transcription factors binding to specific DNA sequences.
- Anticancer drugs and therapeutic agents can modulate gene expression by targeting these interactions.
Purpose of the Study:
- To review mechanisms by which small molecules interfere with transcription factor function.
- To summarize recent advances in understanding drug interactions with regulatory proteins and DNA.
Main Methods:
- Review of literature on small molecule interactions with DNA and transcription factors.
- Categorization of interference mechanisms: non-covalent DNA binding, covalent DNA modification, and antigene strategies.
Main Results:
- Non-covalent binders (e.g., anthracyclines) compete for DNA binding sites.
- Alkylating agents (e.g., cisplatin) modify DNA, blocking or creating aberrant binding sites.
- Antigene strategies use oligonucleotides/PNA to decoy transcription factors or their binding sites.
Conclusions:
- Small molecules offer diverse strategies to modulate transcription factor activity.
- Understanding these mechanisms is crucial for developing targeted therapies.