Mechanism of Type IA Topoisomerases

Dasgupta, Tumpa; Ferdous, Shomita; Tse‐Dinh, Yuk‐Ching

doi:10.3390/molecules25204769

Cited by 18 publications

(29 citation statements)

References 115 publications

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“…Topological changes in DNA are accomplished by type I topoisomerases, which act by generation of single-strand breaks, and type II enzymes, which accomplish topological transformations via double-strand breaks. There is a wealth of information concerning the biochemical properties of these enzymes, and recent reviews include mechanisms of type 1A enzymes that use a strand passage mechanism ( Dekker et al, 2002 ; Dasgupta et al, 2020 ), type 1B topoisomerases ( Champoux, 2001 ; Pommier et al, 2016 ; Seol and Neuman, 2016 ), and type II enzymes ( Vos et al, 2011 ; Chen et al, 2013 ; Bush et al, 2015 ; Hauk and Berger, 2016 ). The DNA cleavage mechanisms of topoisomerases are summarized in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Sun

Nitiss

Pommier

2022

Front. Mol. Biosci.

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Topoisomerases play crucial roles in DNA metabolism that include replication, transcription, recombination, and chromatin structure by manipulating DNA structures arising in double-stranded DNA. These proteins play key enzymatic roles in a variety of cellular processes and are also likely to play structural roles. Topoisomerases allow topological transformations by introducing transient breaks in DNA by a transesterification reaction between a tyrosine residue of the enzyme and DNA. The cleavage reaction leads to a unique enzyme intermediate that allows cutting DNA while minimizing the potential for damage-induced genetic changes. Nonetheless, topoisomerase-mediated cleavage has the potential for inducing genome instability if the enzyme-mediated DNA resealing is impaired. Regulation of topoisomerase functions is accomplished by post-translational modifications including phosphorylation, polyADP-ribosylation, ubiquitylation, and SUMOylation. These modifications modulate enzyme activity and likely play key roles in determining sites of enzyme action and enzyme stability. Topoisomerase-mediated DNA cleavage and rejoining are affected by a variety of conditions including the action of small molecules, topoisomerase mutations, and DNA structural forms which permit the conversion of the short-lived cleavage intermediate to persistent topoisomerase DNA–protein crosslink (TOP-DPC). Recognition and processing of TOP-DPCs utilizes many of the same post-translational modifications that regulate enzyme activity. This review focuses on SUMOylation of topoisomerases, which has been demonstrated to be a key modification of both type I and type II topoisomerases. Special emphasis is placed on recent studies that indicate how SUMOylation regulates topoisomerase function in unperturbed cells and the unique roles that SUMOylation plays in repairing damage arising from topoisomerase malfunction.

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Section: Introductionmentioning

confidence: 99%

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Sun

Nitiss

Pommier

2022

Front. Mol. Biosci.

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“…A distinct approach to target bacterial topoisomerase I is by using DNA molecules as specific inhibitors. The first step in the catalytic cycle of the enzyme is the recognition of the single-stranded regions in duplex DNA [ 139 ]. A series of 84 bp double-stranded oligonucleotides with variations in the number of bulge bases in a single-stranded loop were synthesized and tested for inhibition of the relaxation activity of E. coli topoisomerase I [ 140 ].…”

Section: Recent Attempts To Discover Novel Bacterial Topoisomerasementioning

confidence: 99%

Type IA Topoisomerases as Targets for Infectious Disease Treatments

2021

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Infectious diseases are one of the main causes of death all over the world, with antimicrobial resistance presenting a great challenge. New antibiotics need to be developed to provide therapeutic treatment options, requiring novel drug targets to be identified and pursued. DNA topoisomerases control the topology of DNA via DNA cleavage–rejoining coupled to DNA strand passage. The change in DNA topological features must be controlled in vital processes including DNA replication, transcription, and DNA repair. Type IIA topoisomerases are well established targets for antibiotics. In this review, type IA topoisomerases in bacteria are discussed as potential targets for new antibiotics. In certain bacterial pathogens, topoisomerase I is the only type IA topoisomerase present, which makes it a valuable antibiotic target. This review will summarize recent attempts that have been made to identify inhibitors of bacterial topoisomerase I as potential leads for antibiotics and use of these inhibitors as molecular probes in cellular studies. Crystal structures of inhibitor–enzyme complexes and more in-depth knowledge of their mechanisms of actions will help to establish the structure–activity relationship of potential drug leads and develop potent and selective therapeutics that can aid in combating the drug resistant bacterial infections that threaten public health.

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“…In contrast, the structure of the C-terminal region that follows the toroidal assembly has been much less explored. The presence of small, presumably DNA-binding domains in tandem has shown structural and functional diversity in the C-terminal region of topoisomerase IA [ 13 ]. Two major types of C-terminal domains, Topo_C_ZnRpt (containing C4 zinc finger) and Topo_C_Rpt (without cysteine), were initially identified in Escherichia coli topoisomerase I (EcTOP1) [ 14 , 15 , 16 , 17 ] and Mycobacterium tuberculosis topoisomerase I (MtbTOP1) [ 8 ], respectively, based on their sequence similarities, including the presence/absence of a zinc finger motif.…”

Section: Introductionmentioning

confidence: 99%

Microbial Type IA Topoisomerase C-Terminal Domain Sequence Motifs, Distribution and Combination

Díaz

Mederos

Tan

et al. 2022

IJMS

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Type IA topoisomerases have highly conserved catalytic N-terminal domains for the cleaving and rejoining of a single DNA/RNA strand that have been extensively characterized. In contrast, the C-terminal region has been less covered. Two major types of small tandem C-terminal domains, Topo_C_ZnRpt (containing C4 zinc finger) and Topo_C_Rpt (without cysteines) were initially identified in Escherichia coli and Mycobacterium tuberculosis topoisomerase I, respectively. Their structures and interaction with DNA oligonucleotides have been revealed in structural studies. Here, we first present the diverse distribution and combinations of these two structural elements in various bacterial topoisomerase I (TopA). Previously, zinc fingers have not been seen in type IA topoisomerases from well-studied fungal species within the phylum Ascomycota. In our extended studies of C-terminal DNA-binding domains, the presence of zf-GRF and zf-CCHC types of zinc fingers in topoisomerase III (Top3) from fungi species in many phyla other than Ascomycota has drawn our attention. We secondly analyze the distribution and combination of these fungal zf-GRF- and zf-CCHC-containing domains. Their potential structures and DNA-binding mechanism are evaluated. The highly diverse arrangements and combinations of these DNA/RNA-binding domains in microbial type IA topoisomerase C-terminal regions have important implications for their interactions with nucleic acids and protein partners as part of their physiological functions.

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Mechanism of Type IA Topoisomerases

Cited by 18 publications

References 115 publications

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

SUMO: A Swiss Army Knife for Eukaryotic Topoisomerases

Type IA Topoisomerases as Targets for Infectious Disease Treatments

Microbial Type IA Topoisomerase C-Terminal Domain Sequence Motifs, Distribution and Combination

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