Study shows how mutational signatures are shaped by DNA repair pathways

A research team from EMBL’s European Bioinformatics Institute (EMBL-EBI), the Wellcome Sanger Institute, and the University of Dundee has examined more than 2700 genomes from C. elegans worms to gain a better understanding on the causes responsible for mutations.

Image Credit: Arturo Agostino.

Recently published in the Nature Communications journal, the researchers’ findings define how the mutations of DNA emerge from the collective action of DNA damage and the incorrect repair mechanisms of the DNA.

The DNA of a cell is always subjected to genotoxins, that is, chemical and physical stresses, that can destroy it and lead to mutations. But the cells have a range of repair mechanisms to repair the DNA lesions right after they emerge.

Sometimes, failure occurs in the restorative repair process, either by failing to identify the DNA lesions altogether or by making additional errors.

A majority of the genotoxins, similar to those present in tobacco smoke, were believed to lead to a special set of mutations in the genome, perceptible as a mutational signature.

Detecting such signatures in cancer allows scientists to trace what caused the damage in the first place, and aid prognosis and treatment by pointing to certain vulnerabilities.”

Nadezda Volkova, PhD Graduate, European Bioinformatics Institute, European Molecular Biology Laboratory

But a majority of the mutational signatures, seen in the cancer genomes, do not appear to be associated with any particular genotoxin, while the rest of them seem to occur from a combination of various factors.

To interpret the origin of these mutational signatures, Volkova and his collaborators tested the impacts of more than 150 combinations of 12 genotoxins on C. elegans worms, the DNA repair mechanisms, of which were either defective or unchanged.

The researchers experimentally showed that the mutational signatures occur from an integrated action of particular repair mechanisms and DNA damage.

DNA repair and mutational signatures

A lot of DNA alterations that we observed in our study occur in human cancer as well, but we found that mutational signatures are more variable than we previously thought.”

Nadezda Volkova, PhD Graduate, European Bioinformatics Institute, European Molecular Biology Laboratory -

The researchers found that different kinds of DNA changes caused by the same genotoxin are usually repaired by different pathways of DNA repair mechanisms, with some being error-free and others being error-prone.

Consequently, based on the repair process, one genotoxin may lead to a wide range of mutational signatures at different rates.

Although a majority of the DNA repair pathways inhibit mutations, they can still cause mutations. For instance, Volkova and his collaborators showed that a specific mechanism, known as translesion synthesis, plays a role in most of the base mutations.

These base mutations are induced by genotoxin exposure as a trade-off for possibly more deleterious and more severe mutations.

A majority of these mild mutations may not be dangerous, but in humans, they can elevate the chances of developing a tumor.

In cancer genomics, there is an implicit expectation that for every signature, one could find a single cause: our analysis challenges that expectation. Behind each pattern, there are at least two unknowns: the damage that occurs and the repair capacity of the cell,”

Moritz Gerstung, Group Leader, European Bioinformatics Institute, European Molecular Biology Laboratory

Bringing together cancer genomics and DNA repair

The molecular mechanisms of the DNA repair pathways are quite well-established; however, the frequency and the precise types of mutations that they can produce, continued to be vague until the application of high-throughput sequencing.

This research integrates whole genome sequencing with an experimental screen to gain a better insight into the causes of mutational signatures. These outcomes have promising implications for research, diagnosis, and treatment of cancer

“Understanding the interplay between DNA damage and repair helps to better gauge the risk of cancer predisposition, and to understand the response to cancer treatment,” stated Bettina Meier, a Senior Research Associate from the University of Dundee.

Today, mutational signatures have turned out to be the pillar of cancer genome analysis as they may provide a deeper understanding of the carcinogens cancer cells that have been subjected to and the perturbed repair mechanisms. But, not all visualized mutational signatures and their separate facets have been completely interpreted.

As such, an experimental method makes sure that the visualized patterns are the direct outcomes of the conditions specified by the researchers. It also helps to figure out how the mutational signatures are jointly shaped by numerous DNA repair mechanisms.

“It took years to generate all these repair defective C. elegans, to systematically expose them to a panel of genotoxins, and to prepare, sequence, and analyze their DNA. It is great to see that experimental work on C. elegans is directly relevant for interpreting cancer genomes,” stated Anton Gartner, Group Leader at the University of Dundee and was recently appointed as Associate Director of the IBS Center for Genomic Integrity at UNIST Ulsan in South Korea.