DNA intrastrand sites and guanine-rich sequences (DNA-G4/ICL)

DNA intrastrand sites and guanine-rich sequences are specific genomic regions that serve as primary targets for several classes of anticancer agents. Guanine-rich DNA is highly susceptible to the formation of covalent adducts, such as the 1,2-intrastrand crosslinks created by platinum-based drugs like cisplatin and oxaliplatin, which distort the DNA helix and block essential processes like replication and transcription (Dasari & Tchounwou, 2014, doi:10.1016/j.ejphar.2014.07.025). Additionally, these sequences can fold into non-canonical four-stranded structures called G-quadruplexes (G4s), which are prevalent in telomeres and oncogene promoters (Rhodes & Lipps, 2015, doi:10.1093/nar/gkv129). G4-stabilizing ligands, such as CX-5461, exploit these structures to induce DNA damage and inhibit the expression of genes like c-MYC, providing a targeted approach to treating various malignancies (Xu et al., 2017, doi:10.1038/ncomms14432). Because these sites are often associated with rapid cell proliferation and genomic instability, they are leveraged as therapeutic vulnerabilities in cancer treatment. However, the lack of absolute sequence specificity can lead to off-target effects and systemic toxicities, necessitating the use of biomarkers like BRCA mutations to identify responsive patient populations. The study of these sites continues to evolve, with new ligands being developed to target specific G4 topologies or DNA-protein interactions at these loci.

Other names

G-quadruplexesG4 DNADNA intrastrand adductsGuanine-rich DNA sequences1,2-intrastrand d(GpG) crosslinksPlatinum-DNA adductsG-rich genomic regions

Platinum-based agents form covalent 1,2-intrastrand crosslinks primarily at adjacent guanine bases, causing significant bending of the DNA helix which inhibits replication and transcription (Dasari & Tchounwou, 2014, doi:10.1016/j.ejphar.2014.07.025). G-quadruplex ligands stabilize non-canonical four-stranded DNA structures formed in guanine-rich regions, leading to the inhibition of telomerase activity, suppression of oncogene transcription (e.g., c-MYC), and induction of DNA damage responses (Rhodes & Lipps, 2015, doi:10.1093/nar/gkv129).