Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI), the University of Dundee and the Wellcome Sanger Institute analyzed over 2700 genomes from C. elegans worms in order to better understand the causes of mutations. Their findings, published today in Nature Communications , characterize how DNA mutations result from the combined action of DNA damage and inaccurate DNA repair mechanisms.
A cell's DNA is constantly exposed to physical and chemical stresses - or genotoxins - that can damage it and cause mutations. However, cells have a myriad of repair mechanisms to fix DNA lesions soon after they arise. Occasionally, the restorative repair process fails, either by making extra errors, or by failing to detect the DNA lesions altogether. This leads to mutations, which are the root cause of cancer.
Many genotoxins, like those found in tobacco smoke, were thought to cause a unique suite of mutations in the genome, recognizable 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, recent Ph.D. graduate at EMBL-EBI
However, many mutational signatures observed in cancer genomes do not seem to relate to any single genotoxin and others appear to result from a combination of factors. To understand the origin of these signatures, Volkova and colleagues tested the effects of more than 150 combinations of twelve genotoxins on C. elegans worms whose DNA repair mechanisms were either unaltered or faulty. The scientists experimentally demonstrated that mutational signatures result from a combined action of DNA damage and specific repair mechanisms. 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," says Volkova.
The scientists found that different types of DNA alterations induced by the same genotoxin are often fixed by different DNA repair pathways, some error-free, others error-prone. As a result, a single genotoxin may leave a variety of mutational signatures at various rates, depending on the repair process.
While most DNA repair prevents mutations, it can also cause them. For example, Volkova and colleagues demonstrated that one particular mechanism, called translesion synthesis, is responsible for the majority of base mutations caused by genotoxin exposure as a trade-off for more severe and potentially more deleterious mutations. While many of these minor mutations may be harmless, in humans they can increase the probability of developing a tumour. Related Stories
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