Topoisomerase mutations

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Goni-Urriza M, Arpin C, Capdepuy M et al (2002) Type II topoisomerase quinolone resistance-determining regions otAeromonas caviae,A. hydrophila, and A. sobria complexes and mutations associated with quinolone resistance. Antimicrob Agents Chemother 46(2) 350-359... 

An extensive database has demonstrated that many chemicals that are positive in this test also exhibit mutagenic activity in other tests. There are, however, examples of mutagenic substances, which are not detected by this test reasons for these shortcomings can be ascribed to the specific nature of the endpoint detected, differences in metabolic activation, or differences in bioavailability. On the other hand, factors which enhance the sensitivity of the bacterial reverse mutation test can lead to an overestimation of mutagenic activity. The bacterial reverse mutation test may not be appropriate for the evaluation of certain classes of chemicals for example, highly bactericidal compounds (e.g., certain antibiotics) and those which are thought (or known) to interfere specifically with the mammalian cell replication system (e.g., some topoisomerase inhibitors and some nucleoside analogues). In such cases, mammalian mutation tests may be more appropriate. 

Type II topoisomerases are essential and function in replication, DNA repair, transcription, and chromosome segregation at mitosis.345,349 Yeast with a top2 mutation dies during mitosis with hopelessly entangled daughter chromosomes.353 A fluorescent antibody to eukaryotic topoisomerase II binds to chromosomes, probably at the bases of the radial loops... 

Spontaneous chromosomal mutation of the target enzymes DNA gyrase (GyrA and GyrB) and topoisomerase IV (ParC and ParE), which can gradually produce an increase in resistance to quinolones. 

Modifications of the standard battery may be necessary for some classes, e.g., antibiotics which are toxic to bacteria or e.g., for compounds like topoisomerase inhibitors which interfere with the mammalian cell replication system. A selection of additional assays is being proposed, further modifications may be acceptable via discussion in the ICH Maintenance Process. Alternative strategies may consider assays like the in vivo Comet assay (single cell gel electrophoresis measuring DNA strand breaks) or gene mutation tests with transgenic animals or in vivo DNA adduct studies. 

DNA can also be a target for alkaloids planar and lipophilic alkaloids, such as berberine and sanguinarine (Figure 1.6) are intercalating compounds that assemble between the stacks of paired nucleotides in the DNA double helix [2,3,18,23]. DNA intercalation can disturb replication, DNA repair, and DNA topoisomerases. Frameshift mutations are one of the adverse consequences of intercalating compounds. Some alkaloids, such as pyrrolizidine alkaloids, aristolochic acids, cycasin, and furoquinoline alkaloids, are known to form covalent adducts with DNA bases. Mutations and tumor formation can be the result of such interactions. DNA alkylation occurs in some alkaloids only after activation by liver enzymes, such as cytochrome p450 oxidases (pyrrolizidine alkaloids, aristolochic acids) [17,18,24]. 

In addition, three enzymes involved in DNA replication, including DNA primases, prokaryotic DNA topoisomerase I and some hexameric DNA helicases, are also classic zinc-ribbon proteins. In bacteriophage DNA primases, mutations of the zinc-binding residues abrogate the synthesis of RNA primers for lagging strand DNA synthesis. Strikingly, each subunit of the mini-chromosomal maintenance (MCM) protein, a heterohexameric helicase that initiates DNA replication in S. cerevisiae, contains an independently folded zinc-ribbon domain that appears to stabilize the dodecameric structure (a dimer of hexamers) of this replication complex. ... 

Etoposide and teniposide are similar in their actions and in the spectrum of human tumors affected. Unlike podophyllotoxin, but like the anthracyclines, they form a ternary complex with topoisomerase 11 and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA. The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death. Cells in the S and G2 phases of the cell cycle are most sensitive to etoposide and teniposide. Resistant cells demonstrate ampMcation of the mdr-1 gene that encodes the P-glycoprotein drug efflux transporter, mutation or decreased expression of topoisomerase 11, or mutations of the p53 tumor suppressor gene, a required component of the apoptotic pathway. 

Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV or by active transport of the drug out of the bacteria. No quinolone-modifying or quinolone-inactivating activities have been identified in bacferia. Resistance has increased after the introduction of fluoroquinolones. 

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