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Researchers from Colin Goding’s lab demonstrate that weakening a transcription factor’s DNA binding affinity in vitro paradoxically increases its function in vivo.

In order to activate transcription – the process by which a gene’s DNA is copied into RNA - transcription factors need to bind the regulatory regions of a gene. A natural assumption is that transcription factors need to bind DNA with high affinity to activate gene transcription. In this paper published in Molecular Cell, Pakavarin Louphrasitthiphol, Robert Siddaway and colleagues from Colin Goding’s lab demonstrate that in fact the opposite of this assumption is true. When studying the transcription factor MITF, which plays a central role in melanoma, the researchers found that chemical modification of MITF by acetylation, which weakened its binding to DNA, actually increased MITF’s occupancy of regulatory sites. The researchers argue that transcription factors need to find regulatory sites against a high background of similar sites in the genome. Modifying MITF and weakening its interaction with DNA releases MITF from this reservoir of background sites and increases the likelihood of its binding to the regulatory site. This redistribution mechanism, controlled by oncogenes such as BRAF, allows fine-tuning of transcription factor availability and the control of genes that can influence tumourigenesis and development.  

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