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Mechanism that leads to DNA mutations in melanoma discovered

9 August 2021
Appeared in BioNews 1107

The mechanism underlying DNA damage that leads to melanoma has been found to be a specific mutation caused by UVB radiation in sunlight.

It was previously believed that like most cancers melanoma, which is a type of skin cancer, arises when DNA damage directly causes a mutation which is then copied to daughter cells during normal cell division. A study at the Van Andel Institute in Grand Rapids, Michigan, has shown instead that UVB damage leads to 'premutations' in DNA by modifying one of the DNA bases.

Professor Gerd Pfeifer, corresponding author of the study, said: 'In melanoma, we've now shown that damage from sunlight primes the DNA by creating 'premutations' that then give way to full mutations during DNA replication.'

The study, published in Science Advances, showed that UVB radiation from the sun caused specific sequences of bases to link together and become unstable. This instability led to a chemical change in one of the bases, cytosine, transforming it into uracil – a chemical base found in RNA but not DNA. When normal cell division occurs, these 'premutations' can lead to the DNA mutations underlying melanoma.

The findings were made possible using a method developed by Professor Pfeifer's group called circle damage sequencing, which can identify which DNA bases are present at damaged regions of DNA. The method involves breaking the DNA at the position of the damage and discarding sections that do not contain damaged bases. The sections containing damage are then replicated until enough DNA material is present to use DNA sequencing.

Previous large-scale sequencing studies have shown that melanoma has the most DNA mutations of any cancer, which can accumulate over years of sunlight exposure before causing the disease. Although less common than other types of skin cancer, melanoma is more likely to spread and invade other tissues, which significantly reduces patient survival.

'In our study, 10-15 minutes of exposure to UVB light was equivalent to what a person would experience at high noon, and was sufficient to cause premutations,' said Professor Pfeifer. 'While our cells have built-in safeguards to repair DNA damage, this process occasionally lets something slip by. Protecting the skin is generally the best bet when it comes to melanoma prevention.'

Going forward, the study authors plan to use similar techniques to investigate other types of DNA damage that lead to other cancers.

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