Interactions with Topoisomerases

Interestingly, nucleolin interacts with several key DNA repair and recombination proteins. First of ah, it interacts with topoisomerase I through its N terminus (Bharti et al, 1996 Edwards et al, 2000). This interaction does not modify the enzymatic activity of topoisomerase I per se, but it could play important role in its predominantly nucleolar localization as it was demonstrated in yeast (Edwards... 

Induction of strand breakage may result from inhibition of topoisomerase. The epi-podophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276) these agents cause strand breakage by inhibiting resealing. The te-cans topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA. 

Isothiazoloquinoline derivative 56 is an antibacterial compound that interacts with topoisomerase II. The enol form 56b is the major tautomer, as was predicted by optimizing the geometries and calculating the heat of formation (A7/f) of both tautomers by means of the semi-empirical molecular orbital AMI method, both in the gas phase and in aqueous solution (Table 11) <1998EJM899>. 

A variety of antibiotics and antineoplastic drugs exert their therapeutic effects by interaction with topoisomerase I and disruption of DNA synthesis during phase of dividing cells. Topoisomerase I is essential for DNA replication and cell growth. The enzyme relieves torsional stress in DNA by inducing reversible single-strand breaks. The interaction of topoisomerase I and certain drugs produces double-strand breaks in DNA that are irreversible and can lead to cell death. 

Mechanisms Etoposide increases degradation of DNA, possibly via interaction with topoisomerase II, and also inhibits mitochondrial electron transport. TTie drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. 

This drug is used in combination therapy for testicular carcinoma. It is a CCS drug that acts in the late S and early phases of the tumor cell cycle via interactions with topoisomerase II. This antimetabolite inhibits DNA polymerase and is one of the most active drugs in leukemias. Although myelosuppression is dose-limiting, the drug may also cause cerebellar dysfunction, including ataxia and dysarthria. 

Fig. 4. Primary structure of reverse gyrases. (A) Schematic representation of reverse gyrase sequence with its two domains comparison of the N-terminal domain with various helicases. elF4A is an eukaryotic initiation factor for translation [J. P. Nielson and H. Trachsel, EMBOJ. 7,2097 (1988)]. PriA is a component of the primosome in bacteria (P Nurse, R. J. DiGate, K. H. Zavitz, and K. J. Marians, Proc. Natl. Acad. Sci. U.S.A. 87,4615 (1990)). Sgsl is a helicase interacting with topoisomerases II and III in yeast [S. Gangloff, J. P McDonald, C. Bendixen, L. Arthur, and R. Rothstein, Mol. Cell Biol. 14, 8391 (1994)]. (B). Amino acid sequences of the helicase motifs in reverse gyrases. x indicates a hydrophobic residue. The sequences shown are a consensus where at least four positions out of six are conserved in reverse gyrases.

Jensen PB, Sorensen BS, Sehested M, Demant EJF, Kjeldsen E, Friche E, Hansen HH. Different modes of anthtacydine interaction with topoisomerase II. Biochem Pharmacol 1993 45 2025-2035. 

This observation has triggered the search for compounds that can inhibit telomerase. Special attention has been given to G-quadruplexes, since telomeres that form stabilized quadruplexes cannot be elongated by telomerase (29). Several intercalating compounds stabilize G-quadruplexes and thus inhibit telomerase among these compounds are acridine alkaloids and anthraquinones (30-32). Recently, some natural alkaloids were found, that can inhibit telomerase. These include ellipticine, a known intercalating substance and experimental anticancer agent. Ellipticine and 9-hydroxyellipticine interact with topoisomerase II... 

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