New understanding of mutation pattern holds potential for more tailored cancer treatment
A team of researchers from the MRC Human Genetics Unit have found that the enzyme TOP1 is an important source of mutations in active genes: February 2022
When mutations occur in DNA they can result in disease, including cancer. Mutations inside genes, especially deletions, are particularly likely to be harmful. Understanding how, where and when mutations occur is fundamental to our understanding of genetics and can inform further research into how best to prevent or treat diseases caused by these genetic changes.
By sequencing the genomes of large numbers of tumours, patterns of mutations or ‘signatures’ can be identified and used to indicate underlying molecular mechanisms, in turn informing personalised medicine and treatments tailored to individual patients.
In this research by the Jackson and Taylor Research Groups, the cause of one such mutation pattern - ID4, a cancer signature characterised by short 2-5 base pair deletions – has been identified for the first time.
The team have found that this mutation signature is caused by the TOP1 enzyme, a protein that normally protects our genome by preventing excessive tension in DNA by cleaving it where it has coiled up and resealing it once tension is relieved.
However, if TOP1 leaves the DNA before resealing the cut, a small piece of DNA can be lost when re-joining occurs, causing a deletion.
The results showed that TOP1 cleavage at genome-embedded ribonucleotides is an important source of small deletions in cancer and in the germline. Because TOP1 more commonly cleaves in active genes, the resulting deletions are more likely to affect gene function.
This important study not only improves our understanding of the natural causes of mutations but also highlights that some cancers - in which ID4 is a key signature - may benefit from treatment with certain drugs, for example PARP inhibitors.
Knowing that TOP1 causes these deletions means that tumours showing this mutation pattern may be more sensitive to particular drugs. So as well as understanding how these mutations occur, these findings could in future lead to improved treatment for certain cancers.
- Signatures of TOP1 transcription-associated mutagenesis in cancer and germline | Nature - published in Nature, 9 February 2022
- Andrew Jackson Research Group
- Martin Taylor Research Group