The DNA in our cells is susceptible to a barrage of agents that can cause damage, including radiation or toxic substances such as alcohol. Researchers of the Hubrecht Institute (KNAW) in Utrecht, the Netherlands, and the MRC Laboratory of Molecular Biology in Cambridge, U.K., have discovered a new way in which the human body repairs DNA damage caused by a degradation product of alcohol. That knowledge underlines the link between alcohol consumption and cancer.

The work is published in Nature in the paper titled, “Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms.”

When alcohol is metabolized, acetaldehyde is formed. Acetaldehyde, a highly reactive, DNA-damaging metabolite, causes interstrand crosslinking (ICL) in DNA—a dangerous kind of DNA damage. As a result, it obstructs cell division and protein production. Ultimately, an accumulation of ICL damage may lead to cell death and cancer.

The paper’s authors write that cells are protected against acetaldehyde-induced damage by DNA crosslink repair which, when impaired, causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer. But the mechanism of the acetaldehyde-induced DNA damage remains unknown.

Defense against DNA damage

Thankfully, every cell in our body possesses a toolkit with which it can repair this type of damage to the DNA. The first line of defense against ICLs caused by acetaldehyde is the ALDH2 enzyme, that largely breaks down acetaldehyde before it causes any harm. However, not everyone profits from this enzyme—about half of the Asian population, more than two billion people worldwide, possess a mutation in the gene coding for this enzyme. Because they are not able to break down acetaldehyde, they are more prone to develop alcohol-related cancer.

New line of defense

Scientists explored the second line of defense against alcohol-induced ICLs: mechanisms that remove the damage from the DNA. The investigators studied these mechanisms using protein extracts made from the eggs of the clawed frog (Xenopus laevis). They generated acetaldehyde-induced DNA interstrand crosslinks and determined their repair mechanism in Xenopus egg extracts.

By using these extracts to repair an ICL formed by acetaldehyde, they discovered the existence of two mechanisms—replication-coupled pathways—that repair ICL damage: the previously known FA pathway which, the authors noted, “operates using excision—analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin.”

The team also identified a novel, faster route that “requires replication fork convergence, but does not involve DNA incisions—instead the acetaldehyde crosslink itself is broken.” More specifically, the Y-family DNA polymerase REV1 “completes repair of the crosslink, culminating in a distinct mutational spectrum.”

These two mechanisms differ from each other: in the FA pathway, the DNA is cut to remove the ICL, whereas the enzymes in the newly discovered route cut the crosslink itself. These results, the authors noted, “define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.”

Specific damage

With this research, the scientists provide a mechanistic sneak peek in the process of DNA damage repair. “We now know that there are multiple ways in which the body can repair ICLs in the DNA,” said co-lead author Puck Knipscheer, PhD, group leader at the Hubrecht Institute. She thinks that this type of research may lead to a better understanding of treatment for alcohol-related types of cancer. “But before we can do that, we first have to know exactly how this novel mechanism for ICL repair works.”

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