Assumption undone

Transcription is step one in gene expression. To start the process, proteins known as transcription factors 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 a team led by Ludwig Oxford’s Colin Goding has demonstrated, using the melanoma-associated transcription factor MITF as a model, that this isn’t always true. They showed that a chemical modification to MITF known as acetylation, which weakens its binding to DNA, actually increases MITF’s occupancy of regulatory sequences. The researchers argue that transcription factors need to find regulatory sites against a high background of similar, but low affinity, sites in the genome. Weakening MITF’s DNA-binding releases it from this reservoir of background sites and so increases the likelihood of its binding to its actual regulatory sites. This explains their finding that a low-DNA-binding-affinity MITF mutation that mimics acetylation supports melanoma development and drives tumorigenesis, whereas a high-affinity mutant resistant to such acetylation does not. 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. The study was published in June in Molecular Cell.

This article appeared in the December 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).



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