Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms
The DNA in human 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 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.
When alcohol is metabolized, acetaldehyde is formed. Acetaldehyde, a highly reactive, DNA-damaging metabolite, causes interstrand crosslinking in DNA – a dangerous kind of DNA damage. As a result, it obstructs cell division and protein production. Ultimately, an accumulation of interstrand crosslinking damage may lead to cell death and cancer.
Every cell in the human body possesses a toolkit with which it can repair this type of damage to the DNA. The first line of defense against cell and DNA damage 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.
Scientists explored the second line of defense against alcohol-induced DNA damage and cell death: mechanisms that remove the damage from the DNA.
With this research, the scientists provide a peek into the process of DNA damage repair.
We now know that there are multiple ways in which the body can repair interstrand crosslinking in the DNA,” said co-lead author Puck Knipscheer, PhD, group leader at the Hubrecht Institute, according to GenEn News.
But before we can do that, we first have to know exactly how this novel mechanism for ICL repair works.”
This type of research may lead to a better understanding of treatment for alcohol-related types of cancer.
Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers. 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.
The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question.
Here the researchers generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. They find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision—analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks.
The second repair mechanism requires replication fork convergence, but does not involve DNA incisions – instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.