Diversity and Functions of Type II Topoisomerases

Sutormin, Dmitry; Galivondzhyan, Alina; Polkhovskiy, Alexander V.; Kamalyan, Sofia O.; Severinov, Konstantin; Dubiley, Svetlana

doi:10.32607/actanaturae.11058

Cited by 15 publications

(4 citation statements)

References 242 publications

(237 reference statements)

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“…Top I catalyzes the conversion of the DNA topology by introducing single-strand breaks into the DNA molecule during basic cellular processes such as DNA replication, transcription, recombination, repair and chromatin remodeling ( Parchment and Pessina, 1998 ; Giovanni et al, 2008 ). Top II is able to cleave ds DNA and support more complex interconversions of the DNA topology by an ATP- dependent strand passage mode in transcription, replication, and segregation of chromosomes processes during cell division ( Sutormin et al, 2021 ). Due to their crucial roles in replication and transcription, Top I and Top II are attractive clinical molecular targets for cancer therapy by camptothecin series and doxorubicin series of antineoplastics agents, respectively.…”

Section: Methodsmentioning

confidence: 99%

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review

Mou

Deng

et al. 2022

Front. Pharmacol.

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Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed.

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Section: Methodsmentioning

confidence: 99%

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review

Mou

Deng

et al. 2022

Front. Pharmacol.

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“…The double helical nature of DNA causes the accumulation of positive supercoils ahead of transcription bubbles and replication complexes and negative supercoils ( Figure 1 ) or precatenanes behind [ 18 , 19 ]. Topoisomerases are essential enzymes that can modify the topology of DNA by creating temporary DNA-strand breaks in one (type I) or both (type II) DNA-strands [ 18 , 20 , 21 ]. Topoisomerases are needed to relax the positive supercoils that accumulate ahead of transcription bubbles and replication forks and to remove negative supercoils and precatenanes and catenanes that would otherwise accumulate behind transcription bubbles and replication forks [ 18 , 19 , 21 , 22 ].…”

Section: Dna Topoisomerases Anti-cancer Drugs and Otismentioning

confidence: 99%

Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?

Bax

Sutormin

McDonald

et al. 2022

IJMS

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Topoisomerases are essential enzymes that recognize and modify the topology of DNA to allow DNA replication and transcription to take place. Topoisomerases are divided into type I topoisomerases, that cleave one DNA strand to modify DNA topology, and type II, that cleave both DNA strands. Topoisomerases normally rapidly religate cleaved-DNA once the topology has been modified. Topoisomerases do not recognize specific DNA sequences, but actively cleave positively supercoiled DNA ahead of transcription bubbles or replication forks, and negative supercoils (or precatenanes) behind, thus allowing the unwinding of the DNA-helix to proceed (during both transcription and replication). Drugs that stabilize DNA-cleavage complexes with topoisomerases produce cytotoxic DNA damage and kill fast-dividing cells; they are widely used in cancer chemotherapy. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs) have given drugs that stabilize DNA-cleavage complexes specificity by linking them to either: (i) DNA duplex recognizing triplex forming oligonucleotide (TFO-OTIs) or DNA duplex recognizing pyrrole-imidazole-polyamides (PIP-OTIs) (ii) or by conventional Watson–Crick base pairing (WC-OTIs). This converts compounds from indiscriminate DNA-damaging drugs to highly specific targeted DNA-cleaving OTIs. Herein we propose simple strategies to enable DNA-duplex strand invasion of WC-OTIs giving strand-invading SI-OTIs. This will make SI-OTIs similar to the guide RNAs of CRISPR/Cas9 nuclease bacterial immune systems. However, an important difference between OTIs and CRISPR/Cas9, is that OTIs do not require the introduction of foreign proteins into cells. Recent successful oligonucleotide therapeutics for neurodegenerative diseases suggest that OTIs can be developed to be highly specific gene editing agents for DNA lesions that cause neurodegenerative diseases.

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“…(1) They remodel DNA through a multistep process that results in the passage of a complete double stranded DNA molecule, the T-segment DNA (tDNA), through a transient double-stranded break in a second DNA molecule, the G-segment DNA (gDNA). (10) The structure of the Saccharomyces cerevisiae TopoII complex is a multidomain architecture that can be divided into three major regions (Figure 1) (11). The ATPase domains are built from the GHKL (named for gyrase, HSP90, histidine kinase, and MutL) and transducer domains and contain an ATP binding site that is the location of nucleotide binding and hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

Modeling Allosteric Mechanisms of Eukaryotic Type II Topoisomerases

Evoli

Kariyawasam

Nitiss

et al. 2023

Preprint

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Type II topoisomerases (TopoIIs) are essential enzymes involved in critical nuclear processes such as genome organization, chromosome segregation, and various DNA metabolic events. As large, homodimeric complexes, they undergo a complex ATPase cycle that regulates capturing and passing one DNA double-helix through a second, cleaved DNA molecule. To date, the molecular-level details of how information about the bound nucleotide state is transmitted over vast ranges in the TopoII complex, and how protein substitutions disrupt these mechanisms, remain largely unknown. Here, we conducted extensive molecular dynamics simulations of the yeast TopoII enzyme in multiple nucleotide-bound states and with various amino acid substitutions. Our results reveal remarkable flexibility in the ATPase domains on the sub-microsecond timescale, with dynamics modulated by the identity of the bound nucleotides and the presence of local and distant amino acid substitutions. We identified specific allosteric networks that transmit information as the complex progresses through the hydrolysis cycle that involve residues within the protein and the bound DNA molecule. Notably, amino acid substitutions weakened many of these pathways. Collectively, our findings provide crucial molecular-level insights into the control of the TopoII catalytic cycle through nucleotide binding and hydrolysis and shed light on how mutations may disrupt this process.

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Diversity and Functions of Type II Topoisomerases

Cited by 15 publications

References 242 publications

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review

Structural modifications of berberine and their binding effects towards polymorphic deoxyribonucleic acid structures: A review

Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?

Modeling Allosteric Mechanisms of Eukaryotic Type II Topoisomerases

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