An international team of scientists has presented the results of a study on the mechanisms of DNA damage that turn into mutations and lead to carcinogenesis. It is found that a lot of mutations are caused not by errors in DNA duplication, as was previously considered, but by damage to the fragile molecule before duplication.

The idea came from bio information scientists in leading institutions in the USA, France and Russia. It was confirmed during the experimental part of the work. The key role in this work was played by Natalia Akkuratova, a research engineer at the Institute of Translational Biomedicine, St Petersburg University. The findings are published in Nature Genetics.

It is generally believed that mutations occur: either as a result of errors in the process of DNA replication – the strand duplication that occurs before cell division; or because of errors during its reparation – the process of “repairing” the damage. Another potential source of mutations is unrepaired DNA damage that can occur under the influence of mutagens. For example, ultraviolet leads to melanoma.

This study has shown that a significant part of mutations arises as a result of DNA damage that occurs before replication. An elegant bioinformatics analysis has shown that, although DNA damage is formed on the leading and lagging strands with equal probability, they more often become mutations on the lagging strand. This process leads to hereditary and cancer mutations.

Natalia Akkuratova, a research engineer, the Institute of Translational Biomedicine, St Petersburg University

Since the bioinformatics analysis showed that replication matter interacts with DNA damage, the scientists decided to test this result experimentally. They increased the time lag between induction of damage (in this case, by ultraviolet irradiation) and replication, to give the cells more time for reparation.

The study is supported by the grant of the Russian Science Foundation No 16-15-10273.

To do this, Natalia Akkuratova conducted the following experiment by taking two groups of fibroblasts (connective tissue cells). She irradiated an experimental group with ultraviolet and received a model of melanoma. The other group was not irradiated.

Then Natalia divided each group into two other subgroups. She added roskovitin, a substance that stops cell division, to one of the control and experimental subgroups.  The cells in the second group were divided normally.

“Finally, it has been found that the two-day delay in cell division reduced by 30 times the number of mutations caused by ultraviolet.  It confirmed the proposed theory: the accumulation of mutations caused by DNA damage mainly occurs during replication. A refined understanding of the mechanisms of mutagenesis will make it possible in the future to better understand the development of cancer. It means that this will enable us to develop more effective means of treating and preventing it,” said Natalia Akkuratova.