Medical Perspectives: DNA Replication

You will never encounter a patient suffering due to an inborn error in the basic machinery that executes DNA replication. This does not mean that such a faulty instruction manual never gets issued, just that any zygote given such will not proceed beyond a few cell divisions.

Nonetheless there is medical relevance. Selectively inhibiting DNA synthesis may be used in treating cancer and in killing pathogen via antibiotic.

Inhibiting DNA synthesis can kill a cell. Because of the need to faithfully replicate the genome during cell division the eukaryotic cell very carefully works towards and monitors the successful action of the DNA replication machinery. It will not allow the process to begin unless the genome is judged intact. It will not allow the cell to divide unless the process has completed successfully. A normal cell that starts to replicate its genome but does not finish will apoptose due to the action of the cell-cycle checkpoint machinery. The fast proliferation of cancer cells compared to other cells in the body presents medicine with one of the very few general therapy targets in cancer treatment. Both radiation and most chemotherapies are genotoxins. They work by damaging DNA. If severe enough, the damage triggers apoptosis in dividing cells, leading to the preferential death of cancer cells. But other cells in the body are also dividing. The side-effects of such therapies are often severe.

The quinolone family of antibiotics, which includes the commonly used Ciprofloxacin, work by selectively inhibiting bacterial type II topoisomerases, mostly DNA gyrase. They allow the enzymes to make double-stranded DNA breaks, but prevent it from rejoining the strands. The antibiotic essentially leads one of the bacteria’s own enzymes to fragment its genome.

Telomeres and telomerase function pop up in medical contexts. Most somatic cells in the body do not express telomerase function. As a result, the chromosome ends shorten at every division in such a cell. This is the reason why most isolated cells can only be grown for a limited number of cycles during tissue culture (primary cell cultures). Once they cannot fully replicate their genomes, they stop dividing and become senescent. During tumor progression, cancer cells reactivate their telomerase function, taking a critical step towards immortality. This difference is a potential chemotherapy target. Conversely, individuals with an inherited deficiency in telomere maintenance (they bear one null-mutant allele of one of a handful of genes encoding products that function in telomere maintenance) suffer from dyskeratosis congenita. They usually die from bone marrow failure - essentially a stem cell failure in a critical system.