Double-stranded DNA and telomeric G-quadruplex DNA (dsDNA/G4-DNA)

Telomeric DNA consists of double-stranded regions ending in a single-stranded 3' overhang composed of tandem TTAGGG repeats (Source: Nature Reviews Drug Discovery, 2017). These repeats can fold into four-stranded structures known as G-quadruplexes (G4), which play a critical role in protecting chromosome ends and regulating telomerase access (Source: Nucleic Acids Research, 2020). While double-stranded DNA (dsDNA) is the primary carrier of genetic information and a traditional target for cytotoxic chemotherapy, G-quadruplexes have emerged as a specific therapeutic target due to their prevalence in oncogene promoters and telomeres (Source: Journal of Medicinal Chemistry, 2021). Drugs targeting these structures, such as CX-5461, often aim to stabilize the G-quadruplex, thereby inhibiting telomerase activity or inducing replication stress and DNA damage specifically in cancer cells (Source: Cancer Discovery, 2017). However, achieving selectivity for G4 over the vast excess of genomic dsDNA remains a significant challenge in drug development to minimize off-target genotoxicity (Source: Trends in Pharmacological Sciences, 2012). Targeting these DNA forms is primarily explored in oncology to trigger apoptosis in rapidly dividing cells that rely on telomere maintenance for immortality (Source: Nature Reviews Cancer, 2002).

Other names

dsDNAG-quadruplex DNAG4-DNATelomeric DNATTAGGG repeatsTelomeric G-quadruplex

Drugs targeting these DNA structures act through various mechanisms including DNA intercalation, covalent alkylation, and the stabilization of G-quadruplex secondary structures, which collectively lead to the inhibition of telomerase, induction of the DNA damage response, and subsequent cell cycle arrest or apoptosis.