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Mutagenic properties of topoisomerase-targeted drugs
1Auckland Cancer Society Research Centre, University of Auckland Medical School, Private Bag 92019, Auckland, New Zealand. b.baguley@auckland.ac.nz
Abstract:
Topoisomerases maintain DNA structure by relieving torsional stress occurring in DNA during transcription, replication and cell division. Topoisomerases are of two main types, causing transient breaks in one (type I) or both (type II) and strands of DNA, and a number of clinical anticancer drugs are thought to act by inhibiting religation of these transient breaks. Topoisomerase II appears to have a close association with the SMC (stable maintenance of chromosomes) family of proteins involved in organisation of the chromatin in a series of loops on the proteinaceous chromosomal scaffold. Inhibition of topoisomerase II function can result in deletions of such loops, probably mediated by reciprocal exchange of topoisomerase subunits. Disruption of topoisomerase I and/or II function during DNA replication results in smaller DNA deletions and other mutations, probably arising from non-homologous recombination. Inhibition of topoisomerase II action during mitosis and meiosis can cause incomplete separation of chromatids and chromosomes, with the consequent production of genomic mutations. Topoisomerase-mediated mutagenicity is important because it can lead not only to drug resistance but also to drug-induced secondary cancers. Mutagenicity of topoisomerase-directed agents has been underestimated in the past, since these drugs are not usually capable of reacting covalently with DNA and usually have low mutagenicity in microbial assays.
Insights
Topoisomerases are crucial for DNA integrity during cell processes. Inhibiting these enzymes can cause DNA mutations and genomic instability, potentially leading to drug resistance and secondary cancers.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Topoisomerases regulate DNA structure by relieving torsional stress during DNA replication, transcription, and cell division.
- Type I and Type II topoisomerases create transient breaks in one or both DNA strands, respectively.
- Many anticancer drugs target topoisomerases by inhibiting the religation step.
Purpose of the Study:
- To investigate the role of topoisomerases in maintaining DNA structure and the consequences of their inhibition.
- To explore the association between topoisomerase II and the SMC protein family in chromatin organization.
- To understand the mutagenic potential of topoisomerase-directed agents.
Main Methods:
- The study reviews existing literature on topoisomerase function and the effects of their inhibition.
- Analysis of mechanisms by which topoisomerase inhibition leads to DNA deletions and mutations.
- Examination of the link between topoisomerase function, chromatin structure, and genomic stability.
Main Results:
- Inhibition of topoisomerase II can lead to DNA loop deletions, potentially mediated by subunit exchange.
- Disruption of topoisomerase I/II during replication causes DNA deletions and mutations via non-homologous recombination.
- Impaired topoisomerase II activity during cell division results in chromosomal segregation errors and genomic mutations.
Conclusions:
- Topoisomerase-mediated mutagenicity contributes to drug resistance and secondary cancers.
- The mutagenic effects of topoisomerase inhibitors may be underestimated due to their non-covalent DNA interaction and low microbial mutagenicity.