New insights into alcohol-related DNA damage and cancer risk

Alcohol consumption leads to the formation of a toxic compound called acetaldehyde, which damages DNA. A research team from IOCB Prague has now described in detail how cells repair this damaged genetic information. Their study provides new insight into the link between alcohol consumption and the development of cancer. The findings were published in the Nature Portfolio journal Communications Biology.

The researchers focused on Fanconi anemia, a rare inherited disorder characterized by a failure to repair specific types of DNA damage. In this condition, the two strands of DNA literally become stuck to each other, blocking the replication of genetic information and preventing the cell from dividing. If the damage is not repaired, severe chromosomal instability occurs, leading either to uncontrolled cell growth – cancer – or to cell death.

Dr. Jan Šilhán of IOCB Prague explains: "Patients with Fanconi anemia suffer from disorders of blood formation and have a higher incidence of cancer. It turns out that DNA damage caused by alcohol, more precisely by its toxic metabolite acetaldehyde, which reacts directly with DNA, can cause similar problems in people who do not have Fanconi anemia."

The researchers chemically synthesized this type of DNA damage and examined the enzymes capable of recognizing and repairing it. They discovered that the SXE enzyme complex (SLX4–XPF–ERCC1) can precisely cut out the damaged site, thereby initiating DNA repair. This enzymatic system is far more versatile than previously thought: in addition to damage caused by alcohol, it can also repair defects induced by chemotherapy and other toxic agents.

The first author of the study, PhD student Jana Havlíková of IOCB Prague, adds: "These findings may help explain why some people are more susceptible to alcohol-related cancers than others. The differences may lie in how efficiently their DNA repair mechanisms work."

In a laboratory in the United Kingdom where Jan Šilhán previously worked, his former colleagues carried out experiments in mice with defects in both a DNA repair pathway and in the enzyme responsible for breaking down toxic acetaldehyde. This combination created conditions equivalent to Fanconi anemia. The animals showed major damage to blood formation and DNA and frequently developed malignant tumors. In one case, the researchers even found that when a pregnant mouse was unable to metabolize acetaldehyde, the developing embryo was also severely damaged.

Taken together, the findings suggest that individuals who carry genetic mutations affecting DNA repair and at the same time have a reduced ability to detoxify acetaldehyde face a significantly higher risk of developing cancer after consuming even small quantities of alcohol. "The message is clear: alcohol damages DNA. We may have described the mechanism that cells use to repair this kind of DNA damage, but this is still basic research, and there is no miracle pill," says Jan Šilhán.