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.
With the discovery of the DNA destroying metabolite, 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 has the capacity to repair the ICL formed. However, when ICL 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 anaemia (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 alcohols can results in severe symptoms such as early aging and failure of hematopoiesis system due to bone marrow pathology. The susceptibility to ICL formation and defective repair in Fanconi Anemia has been known 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 find 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 has been found to be 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 diseases treatment.