Summary: The DNA damage done by tobacco smoking has been shown at high resolution throughout the genome in a new study published in the journal Proceedings of the National Academy of Sciences.
Cigarette smoking is extremely harmful down to the DNA—a fact that scientists have known for years now. However, for the first time, a team of researchers from UNC School of Medicine has developed an effective method to map the DNA damage at high resolution. DNA maps such as these are useful at providing a deeper understanding of the origin of cancers that arise from tobacco smoking. The genetic information will help scientists pinpoint why some people are more susceptible or resistant to cancers. Furthermore, prevention of these cancers might also be possible through the maps.
Assisted by Nobel laureate Aziz Sancar, the scientists started by using their technique to map specific regions on the genome where a common form of DNA damage was being undone (through a repair process). Thereafter, they proceeded to do the same with the areas subject to damage by benzo[α]pyrene (BaP), a potent chemical carcinogen that is responsible for around 30% of cancer deaths in the US, explains Sancar. The study is considered as a big step forward to have a “genome-wide map” that demonstrates the harm caused by the compound.
BaP is a carbon-rich hydrocarbon that constitutes a serious hazard to humans. It is released from the burning of organic compounds, and one of the worst ways in which it finds its way into human tissue is through smoking cigarettes. When toxic hydrocarbons flow in our blood, enzymes will attempt to break them down into safer molecules. However, this ends in a nightmare for BaP: instead of producing harmless molecules from these reactions, another more harmful compound is made, named benzo[α]pyrene diol epoxide (BPDE). The BPDE chemically reacts with DNA, attaching itself in a strong bond (an adduct) with DNA component known as guanine (pictured above). This adduct not only prevents the genes from making the appropriate proteins but also hinders the process of DNA replication, all of which leads to diseases, depending on the region where the adduct happens. Lead author of the study, Wentao Li, explains that cancer-causing permanent mutation can occur if a BPDE adduct at a tumour suppressor gene remains unrepaired.
The new method allows for the mapping of DNA damage caused by BaP, and for the identification of the genomic sites where repair is being initiated. The type of repair documented entails the removal of the affected DNA strand. DNA surgery for you. Then, the missing DNA section is added again while the excised DNA remains lying around waiting to be degraded. This piece of DNA is the target of the new technique: the scientists aim at finding it and sequencing it to draw a map of the genome. A complete map is, thus, generated, showing the sites where DNA repair has been done.
Through this knowledge, Sancar and his colleagues were able to find hotspots where the risk of BPDE-induced mutation is higher.
“Understanding this bias in repair should help us better understand why exposures to toxins such as BaP tend to cause certain gene mutations,” says Li.
It is hoped that the new technique will help scientists determine the dose of toxin that prevents the repair process to be done, and which gene variation makes people better or worse at repairing DNA damage. More importantly, this might help them develop new therapies to treat patients.
Furthermore, the new method can be used on any form of DNA damage involving this type of repair, says Sancar.
“I’m certain that all this information will lead to a better understanding of why certain people are predisposed to cancer, and which smoking-related mutations lead to lung cancer specifically,” says Sancar.