The study shows that chromatin and the factors regulating it prevent the formation of DNA-RNA hybrids, a source of genomic instability associated with cancer. These hybrids block replication, resulting in increased chromosomal cleavages and collisions between transcription and replication.
The research has shown that chromatin is a first barrier to protect the integrity of the genome. This has been observed in analyses of the silencing of various chromatin remodelling factors in tumour cell cultures.
In a study comparing their data with genome databases of tumour cells, they found that genome sites enriched in DNA-RNA hybrids match the sites with the highest frequency of mutations found in tumour cells. The work thus reveals for the first time that there is a direct association between DNA-RNA hybrids and cancer-associated mutations, suggesting that they are a risk factor in the development of tumours.
Aguilera's lab has pioneered studies of the role of DNA-RNA hybrids in the development of genetic instability, and this new paper not only offers a better understanding of cellular control of hybrids and their regulation by epigenetic factors, but also points to the possibility that levels of DNA-RNA hybrids in cells could be used as a potential indicator of carcinogenic risk.
The paper, published in the journal Nature Communications, was funded by the Spanish State Research Agency and the European Research Council, among others.
