RFC Inhibitors

Chemical inhibitors of the Replication Factor C (RFC) exhibit their effects through various mechanisms that impede DNA replication and repair processes. Aphidicolin, a tetracyclic diterpene antibiotic, specifically targets DNA polymerases α and δ, which are critical for DNA synthesis. RFC, which is essential for sliding the PCNA clamp onto DNA, thereby facilitating replication, is functionally hindered due to the inhibition of DNA polymerase δ by Aphidicolin. Similarly, Hydroxyurea limits the availability of deoxyribonucleotide pools by inhibiting ribonucleotide reductase, a key enzyme for DNA synthesis. This reduction in nucleotide availability restricts the activity of RFC, as it requires nucleotides for PCNA clamp loading and subsequent DNA synthesis. On the other hand, Gemcitabine, a nucleoside analog, gets incorporated into DNA, thus disrupting the natural progression of DNA replication where RFC is operative.

Further inhibitory effects on RFC come from agents that induce DNA damage. β-lapachone, a natural quinone, interferes with DNA repair mechanisms, which are contingent upon the functionality of RFC. Topoisomerase inhibitors such as Camptothecin and Etoposide create single-strand and double-strand DNA breaks, respectively. These breaks in the DNA structure render the substrate unsuitable for RFC's action. Likewise, DNA intercalators and cross-linking agents, like Doxorubicin and Mitomycin C, respectively, distort the DNA helix, thereby obstructing the RFC-mediated loading of PCNA. Cisplatin exerts its effect by forming DNA adducts and intrastrand crosslinks, which pose a block to the replication machinery, including RFC. Actinomycin D binds to DNA and inhibits transcriptional elongation, indirectly affecting RFC which is dependent on the proper structure and integrity of DNA for its function. Bleomycin, which cleaves DNA strands through oxidative damage, also indirectly impedes RFC's ability to operate by damaging the very DNA it acts upon. Fludarabine, as a purine analog, disrupts both DNA polymerization and nucleotide synthesis, further impeding the action of RFC in DNA replication.