Drug Discovery Opinion

Scientists at Johns Hopkins School of Medicine set out to systematically map protein-DNA interactions across the human genome using a combination of bioinformatics and a protein-microarray strategy. Their exploration of the protein-DNA interactome identified over 17,000 interactions between 460 DNA sequences predicted to regulate transcription and 4191 proteins of varied functional classes. As well as finding known transcription factors (TFs), the work uncovered a large number of previously uncharacterised TFs. Of the unconventional DNA-binding proteins, over 300 exhibited sequence-specific DNA-binding.

One example of the sequence-specific DNA binders identified was ERK2 (MAP kinase-1), a serine/threonine kinase involved in cellular signalling. The Johns Hopkins team found that ERK2 is a transcriptional repressor of interferon-γ inducible genes and that this function is independent of its catalytic kinase activity. Whilst ERK2 has been extensively studied because of its importance in regulation of cellular proliferation, this unexpected additional role of ERK2 adds another level of complexity. Knowledge of the transcriptional repressor function may shed new light on knock-out experiments with ERK2.

The study, published in the journal Cell, examined only a fraction of the human proteome, raising the possibility that there may be thousands of proteins that also function as transcription factors. Certainly something else to consider in drug discovery when your enzyme inhibitor doesn’t do the same as the knockout!

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