How weak binding to DNA boosts the function of a regulator of gene expression

Researchers from Ludwig Oxford’s 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—proteins known as transcription factors must bind the regulatory regions of a gene. It is typically assumed that the more tightly they bind these regulatory DNA sequences, the better they perform their function.

Now, in a paper published in Molecular Cell, Pakavarin Louphrasitthiphol, Robert Siddaway and colleagues from Colin Goding’s lab demonstrate that this is not always the case. 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 sequences. The researchers argue that transcription factors need to find regulatory sites against a high background of similar sites in the genome. The weakening of MITF’s interaction with DNA releases it from this reservoir of background sites and so 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 tumorigenesis and development.


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