DNA phosphodiester backbone (DNA backbone)

The DNA phosphodiester backbone is the structural framework of deoxyribonucleic acid, composed of alternating phosphate groups and deoxyribose sugars linked by covalent phosphodiester bonds [Wikipedia, https://en.wikipedia.org/wiki/DNA]. In replicating cells, the DNA is unwound and more accessible, making the backbone and its associated bases primary targets for various cytotoxic agents [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703326/]. Many traditional chemotherapies, including alkylating agents and platinum-based coordination complexes, exert their effects by forming covalent adducts or cross-links with DNA, which interfere with essential cellular processes such as DNA replication and transcription [StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK544284/]. By inducing significant DNA damage and structural instability, these interactions trigger cell cycle arrest and apoptosis in rapidly dividing cells [MDPI, https://www.mdpi.com/2072-6694/14/10/2479]. However, because these agents target DNA in all dividing cells, they often cause significant side effects in healthy tissues with high turnover rates, such as bone marrow and the gastrointestinal tract [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053155/].

Other names

Sugar-phosphate backboneDNA phosphate backboneDeoxyribonucleic acid backbonePhosphodiester framework

Drugs targeting the DNA backbone primarily act through covalent modification, such as alkylation or the formation of platinum-DNA adducts, which result in interstrand or intrastrand cross-links [StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK544284/]. These modifications physically obstruct DNA and RNA polymerases, leading to replication fork stalling and strand breaks [MDPI, https://www.mdpi.com/2072-6694/14/10/2479]. Additionally, certain agents like bleomycin induce oxidative stress that directly cleaves the phosphodiester bonds, while intercalators like doxorubicin wedge between base pairs to stabilize the DNA-topoisomerase complex, preventing the re-sealing of the backbone during replication [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137001/].