DNA and DNA-associated enzymes (DNA/DNA-enzymes)

DNA and DNA-associated enzymes represent a broad class of therapeutic targets essential for the survival and proliferation of rapidly dividing cells, particularly in the context of malignancy (Alberts B, et al., Molecular Biology of the Cell, 2002). This group includes the genomic DNA itself, along with critical enzymes such as DNA polymerases, topoisomerases, helicases, and ligases that facilitate replication and maintain structural integrity (Pommier Y, Nat Rev Cancer, 2006). In cancer therapy, these targets are exploited because malignant cells often possess defective cell cycle checkpoints and an increased dependency on DNA repair pathways to survive high levels of replication stress (Lord CJ & Ashworth A, Nature, 2012). Pharmacological intervention typically involves DNA-damaging agents like alkylators and crosslinkers, or enzyme inhibitors that stall the replication fork and induce apoptosis (Dasari S & Tchounwou PB, Eur J Pharmacol, 2014). While these strategies are cornerstone treatments for various solid and hematological tumors, they also impact healthy proliferating tissues such as bone marrow and intestinal epithelium, leading to significant clinical toxicities (Longley DB, et al., Nat Rev Cancer, 2003). Modern approaches, such as PARP inhibition, aim for synthetic lethality by targeting specific DNA repair deficiencies unique to certain cancers (Bryant HE, et al., Nature, 2005). Additionally, targeting DNA-associated enzymes is a strategy used in antiviral therapy to prevent the replication of viral genomes within host cells (De Clercq E, Nat Rev Drug Discov, 2002).

Other names

DNA replication machineryReplisome componentsDNA repair enzymesProliferation-associated DNA targetsDNA replication and repair machinery

Mechanisms include DNA intercalation, covalent DNA cross-linking, inhibition of Topoisomerase I and II to induce strand breaks, inhibition of DNA polymerases, depletion of nucleotide pools via antimetabolites, and inhibition of PARP to prevent single-strand break repair (Pommier Y, Nat Rev Cancer, 2006; Longley DB, et al., Nat Rev Cancer, 2003).