Correcting DNA Damage From Alcohol Could Be Soon Possible

Alcohol has widespread systemic effects damaging vital organs by various underlying mechanisms. Among these mechanisms, alcohol production of a degradation product with destructive action on the human genetic structure has severe toxic effects. The metabolite links DNA elements of adjacent opposite strands changing their basic structure.

Alcoholic Spirits

Alcoholic Spirits

With the discovery of DNA-destroying metabolites, researchers focused on drugs to reverse the action of the metabolite on the human genome. After the ingestion of alcohol, hepatocytes synthesize acetaldehyde as a by-product of alcohol metabolism.

When acetaldehyde levels rise to a significant amount within the hepatocyte cells, they can become incorporated within the nucleus and react with the DNA strands. This reaction results in the integration of two DNA fragments forming Inter Strand Crosslinks (ICL). In healthy cells, the nucleus can repair the ICL formed. However, when ICLs are formed in large numbers and rapidly, the repair mechanisms can become quickly overwhelmed.

Relation between Fanconi Anemia and ICL

In rare conditions such as Fanconi Anemia, the repair process is incapacitated due to defects in 22 FNAC genes. 22 FNAC genes are responsible for encoding proteins crucial for DNA crosslink repair.

An inability to repair ICLs is linked to the rare genetic disease Fanconi anemia (FA). This condition is caused by mutations in any one of 22 FANC genes, which encode proteins that participate in ICL repair. In such people, intake of small amounts of alcohol can result in severe symptoms such as early aging and failure of the hematopoiesis system due to bone marrow pathology. The susceptibility to ICL formation and defective repair in Fanconi Anemia has been known for more than 50 years but evidence with DNA crosslinks was discovered only a few years back. Since this discovery, researchers have been racing to find possible ways to reverse the action of acetaldehyde on FNA fragments.

Priority was given to finding methods to remove the harmful metabolites of alcohol from the circulation to limit the damage to DNA. Removing acetaldehyde from the system by inactivating it to less harmful isomers or completely harmless acetate was extensively studied in mice. In Asian people, a crucial enzyme ALDH is absent which results in failed conversion of acetaldehyde to its harmless counterparts.

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By inducing breaks on bilateral DNA via the FA pathway, the destructive ICL could be cleared. Unfortunately, this process doesn’t come free of risks as it could result in disastrous reconfiguration of chromosome structure leading to mutations and cancer. In an alternative technique, instead of separating the DNA strand, a cut could be introduced in the crosslink itself preventing DNA damage.

Breakthrough on ICL repair

Some chemotherapy drugs such as cisplatin are known agents to induce ICL formation. Studies have tried to repair damage induced by chemotherapy medications on DNA molecules via analysis of individual DNA lesions. The study made a remarkable finding with the discovery of a unique repair pathway by replicating DNA and removing the ICL by unhooking it from the replicated DNA.

Researchers aim to replicate their findings to synthesize drugs that could induce the repair pathway of DNA replication and ICL unhooking with widespread implications in alcoholic liver disease treatment.

FAQ: Alcohol-Induced DNA Damage and Repair Mechanisms

1. How does alcohol damage DNA?

Alcohol is metabolized into acetaldehyde, which can bind to DNA strands, forming interstrand crosslinks (ICLs) that alter genetic structure and impair DNA function.

2. What are interstrand crosslinks (ICLs)?

ICLs occur when DNA strands become chemically linked, preventing normal replication and repair, which can lead to mutations and cellular dysfunction.

3. What is the connection between Fanconi anemia and alcohol-induced DNA damage?

People with Fanconi anemia (FA) have defective DNA repair mechanisms due to mutations in 22 FANC genes, making them highly susceptible to ICL formation and severe systemic effects from alcohol exposure.

4. Why do some individuals, especially Asians, have a stronger reaction to alcohol?

Many Asian individuals have a deficiency in aldehyde dehydrogenase (ALDH), an enzyme needed to convert acetaldehyde into harmless acetate. This leads to higher acetaldehyde accumulation and increased DNA damage.

5. How are researchers working to repair alcohol-induced DNA damage?

Scientists are exploring drugs that can reverse ICL formation by either breaking the crosslink directly or inducing DNA replication mechanisms that “unhook” the damage without disrupting the entire DNA strand.

6. Can chemotherapy drugs also cause ICLs?

Yes, some chemotherapy agents like cisplatin induce ICLs, and researchers are studying how to repair these DNA lesions, which could have applications for alcohol-induced DNA damage as well.

7. What are the risks of DNA repair therapies?

While inducing DNA breaks to clear ICLs may help remove the damage, it can also lead to chromosomal mutations and cancer if not properly controlled.

8. How could these discoveries help treat alcoholic liver disease?

By developing drugs that enhance DNA repair pathways, scientists hope to mitigate the harmful effects of acetaldehyde, potentially reducing the risk of liver disease in chronic alcohol users.

References

Gallina, I., & Duxin, J. P. (2020). A safe fix for alcohol-derived DNA damage. Nature, 579(7800), 499–500. https://doi.org/10.1038/d41586-020-00462-1

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