What is the mechanism by which the chemical 5-azacytidine enhances gene expression?

Gene expression is the process through which genetic information encoded in a gene is transformed into a functional product, such as a protein or RNA molecule. 5-azacytidine (AZA) is a chemical compound that acts as an analog of the nucleotide cytidine, which is a component of DNA and RNA.

5-azacytidine's main mode of action is by inhibiting DNA methyltransferase enzymes (DNMTs). DNMTs are enzymes responsible for adding a methyl group to the cytosine residues in DNA. 5-azacytidine gets incorporated into the DNA during replication, which occurs when the DNA is copied before cell division. When a DNMT tries to methylate this azacytosine, the enzyme becomes trapped and subsequently degraded. This leads to a reduction in DNA methylation.

DNA methylation is an epigenetic modification that occurs when a methyl group is added to the cytosine residue of a CpG dinucleotide in the DNA. Methylation of a gene's promoter region, a regulatory region located upstream of the gene, typically leads to repression of gene expression. This happens because the methyl groups can block the binding of transcription factors, which are necessary for gene expression, and also facilitate the binding of proteins that compact the DNA, making it less accessible to the transcription machinery.

By inhibiting DNMTs and decreasing DNA methylation, 5-azacytidine can lead to enhanced gene expression. As mentioned earlier, DNA methylation is usually associated with reduced gene expression. When 5-azacytidine causes a decrease in DNA methylation, it can lead to the reactivation of silenced or suppressed genes, resulting in enhanced gene expression. This can be particularly relevant in the context of cancer treatment, as 5-azacytidine can reactivate tumor suppressor genes that have been silenced by hypermethylation. In conclusion, 5-azacytidine enhances gene expression by inhibiting DNA methyltransferase enzymes, leading to a decrease in DNA methylation. This ultimately results in the reactivation of silenced or suppressed genes and increased gene expression.