Research findings could guide treatment which minimises mutations

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Damage to DNA is a major cause of genetic changes and can drive the development of cancer.

The DNA changes or mutations that result from the damage, and the efficiency of damage repair, depends on what the DNA is doing in a cell and how it is packaged.

Most mutations come from trying to copy the damaged DNA. This copying – known as DNA replication – is normally very different for the two DNA strands with one copied as the leading strand and the other as the lagging strand.

A new paper by researchers at the MRC Human Genetics Unit in the Institute of Genetics and Cancer found that despite this difference, both versions of copying are able to bypass damage in exactly the same way.

Mutations can be avoided if damage is removed before the copying takes place. Normally this repair is very accurate and does not make mistakes. However, the researchers found that when damage is clustered together but on opposite DNA strands, this forces the repair machinery to make a mistake and creates a mutation.

These repair-driven mutations seem to be more damaging than the others because they tend to occur next to the places with the best repair – important control sites in DNA and on the strand of DNA encoding for proteins that are most being used by the cell.

These mutations also arise in a cell before it has copied its DNA, so damage that could create a cancer promoting mutation has a chance to make mutant forms of the protein even before a cell has divided, which is not the case for other damage-induced mutations. This may push a cell into dividing that wouldn’t otherwise, allowing it to subsequently grow into a tumour.

Understanding this could help refine treatment with chemotherapeutics which do cause DNA damage, where it might help to minimise these especially important mutations caused by the repair.

Martin Taylor

The paper, entitled Strand-resolved mutagenicity of DNA damage and repair, is published by Nature (Strand-resolved mutagenicity of DNA damage and repair | Nature).

Links

• Martin Taylor Research Group
• Strand-resolved mutagenicity of DNA damage and repair | Nature