Modeling allosteric mechanisms of eukaryotic type II topoisomerases

Evoli, Stefania; Kariyawasam, Nilusha L.; Nitiss, Karin C.; Nitiss, John L.; Wereszczynski, Jeff

doi:10.1016/j.bpj.2024.05.004

Biophysical Journal

2024

DOI: 10.1016/j.bpj.2024.05.004

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Modeling allosteric mechanisms of eukaryotic type II topoisomerases

Stefania Evoli,

Nilusha L. Kariyawasam,

Karin C. Nitiss

et al.

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2024

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Cited by 1 publication

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Genome Instability Induced by Topoisomerase Misfunction

Nitiss,

Bandak,

Berger

et al. 2024

IJMS

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Topoisomerases alter DNA topology by making transient DNA strand breaks (DSBs) in DNA. The DNA cleavage reaction mechanism includes the formation of a reversible protein/DNA complex that allows rapid resealing of the transient break. This mechanism allows changes in DNA topology with minimal risks of persistent DNA damage. Nonetheless, small molecules, alternate DNA structures, or mutations in topoisomerase proteins can impede the resealing of the transient breaks, leading to genome instability and potentially cell death. The consequences of high levels of enzyme/DNA adducts differ for type I and type II topoisomerases. Top1 action on DNA containing ribonucleotides leads to 2–5 nucleotide deletions in repeated sequences, while mutant Top1 enzymes can generate large deletions. By contrast, small molecules that target Top2, or mutant Top2 enzymes with elevated levels of cleavage lead to small de novo duplications. Both Top1 and Top2 have the potential to generate large rearrangements and translocations. Thus, genome instability due to topoisomerase mis-function is a potential pathogenic mechanism especially leading to oncogenic progression. Recent studies support the potential roles of topoisomerases in genetic changes in cancer cells, highlighting the need to understand how cells limit genome instability induced by topoisomerases. This review highlights recent studies that bear on these questions.

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Genome Instability Induced by Topoisomerase Misfunction

Nitiss,

Bandak,

Berger

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

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Modeling allosteric mechanisms of eukaryotic type II topoisomerases

Cited by 1 publication

References 51 publications

Genome Instability Induced by Topoisomerase Misfunction

Genome Instability Induced by Topoisomerase Misfunction

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