Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Saha, Sourav; Huang, Shar-yin N.; Jo, Ukhyun; Zhang, Hongliang; Tse‐Dinh, Yuk‐Ching; Pommier, ﻿Yves

doi:10.1101/2020.03.22.002691

Cited by 2 publications

(4 citation statements)

References 103 publications

(123 reference statements)

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“…The activity of ExoVII appears to be fine-tuned so that it is primed for DNA adducts at the end of 4-nt overhangs, which correspond to trapped type IIA TOPcc in vivo (8,25). We also found that ExoVII can remove DNA gyrase from trapped TOPcc under conditions where the polypeptide is denatured, similar to previous findings for the eukaryotic TDP1 and TDP2 (36)(37)(38)(39)(40)(41). These observations suggest that the substrate binding site of ExoVII is large enough to accommodate the denatured type IIA topoisomerase polypeptide covalently attached to single-stranded 5′-DNA ends.…”

Section: Discussionsupporting

confidence: 88%

“…The eukaryotic TDP enzymes cannot efficiently excise TOPcc unless the TOPcc is first unfolded or digested (10,(36)(37)(38)(39)(40)(41). Hence, we examined whether the tyrosyl nuclease activity of ExoVII is capable of excising native trapped DNA gyrase generated with recombinant DNA gyrase and radiolabeled DNA substrates.…”

Section: Denaturation Of Trapped Dna Gyrase Is Required For Exovii-me...mentioning

confidence: 99%

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Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes

et al. 2021

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The widely used quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases, resulting in irreversible topoisomerase cleavage complexes (TOPcc). Whereas the excision repair pathways of TOPcc in eukaryotes have been extensively studied, it is not known whether equivalent repair pathways for prokaryotic TOPcc exist. By combining genetic, biochemical, and molecular biology approaches, we demonstrate that exonuclease VII (ExoVII) excises quinolone-induced trapped DNA gyrase, an essential prokaryotic type IIA topoisomerase. We show that ExoVII repairs trapped type IIA TOPcc and that ExoVII displays tyrosyl nuclease activity for the tyrosyl-DNA linkage on the 5′-DNA overhangs corresponding to trapped type IIA TOPcc. ExoVII-deficient bacteria fail to remove trapped DNA gyrase, consistent with their hypersensitivity to quinolones. We also identify an ExoVII inhibitor that synergizes with the antimicrobial activity of quinolones, including in quinolone-resistant bacterial strains, further demonstrating the functional importance of ExoVII for the repair of type IIA TOPcc.

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Section: Discussionsupporting

confidence: 88%

Section: Denaturation Of Trapped Dna Gyrase Is Required For Exovii-me...mentioning

confidence: 99%

Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes

et al. 2021

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“…Moreover, the presence of divalent ions cannot compensate for the loss of this arginine residue in G-strand religation, resulting in a dominant lethal cell killing because of the accumulation of topoisomerase I-mediated DNA breaks [ 76 ]. A R338W mutation introduced at the corresponding arginine residue in human topoisomerase IIIβ has been shown to facilitate trapping of the intracellular covalent complex with both DNA and RNA [ 77 ], confirming a similar role for this arginine residue in the cleavage and rejoining of the RNA G-strand.…”

Section: Mechanism Of the G-strand Cleavage And Religationmentioning

confidence: 95%

Mechanism of Type IA Topoisomerases

2020

Self Cite

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Topoisomerases in the type IA subfamily can catalyze change in topology for both DNA and RNA substrates. A type IA topoisomerase may have been present in a last universal common ancestor (LUCA) with an RNA genome. Type IA topoisomerases have since evolved to catalyze the resolution of topological barriers encountered by genomes that require the passing of nucleic acid strand(s) through a break on a single DNA or RNA strand. Here, based on available structural and biochemical data, we discuss how a type IA topoisomerase may recognize and bind single-stranded DNA or RNA to initiate its required catalytic function. Active site residues assist in the nucleophilic attack of a phosphodiester bond between two nucleotides to form a covalent intermediate with a 5′-phosphotyrosine linkage to the cleaved nucleic acid. A divalent ion interaction helps to position the 3′-hydroxyl group at the precise location required for the cleaved phosphodiester bond to be rejoined following the passage of another nucleic acid strand through the break. In addition to type IA topoisomerase structures observed by X-ray crystallography, we now have evidence from biophysical studies for the dynamic conformations that are required for type IA topoisomerases to catalyze the change in the topology of the nucleic acid substrates.

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“…Mutations in TDP2 cause intellectual disability in humans, which is thought to arise from the accumulation of DSBs linked to defective TOP2cc repair [ 59 ]. Interestingly, a self-trapping mutant of another topoisomerase, TOP3B (R338W), was also recently shown to crosslink to 5′ ends of both DNA and RNA [ 60 ]. However, whether endogenous TOP3Bccs arise in cells and the impact of these lesions on DNA or RNA processes are still unknown.…”

Section: Dna-protein Crosslinks: a Diverse Class Of Lesionsmentioning

confidence: 99%

How to fix DNA-protein crosslinks

Kühbacher

Duxin

2020

DNA Repair

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Proteins that act on DNA, or are in close proximity to it, can become inadvertently crosslinked to DNA and form highly toxic lesions, known as DNA-protein crosslinks (DPCs). DPCs are generated by different chemotherapeutics, environmental or endogenous sources of crosslinking agents, or by lesions on DNA that stall the catalytic cycle of certain DNA processing enzymes. These bulky adducts impair processes on DNA such as DNA replication or transcription, and therefore pose a serious threat to genome integrity. The large diversity of DPCs suggests that there is more than one canonical mechanism to repair them. Indeed, many different enzymes have been shown to act on DPCs by either processing the protein, the DNA or the crosslink itself. In addition, the cell cycle stage or cell type are likely to dictate pathway choice. In recent years, a detailed understanding of DPC repair during S phase has started to emerge. Here, we review the current knowledge on the mechanisms of replication-coupled DPC repair, and describe and also speculate on possible pathways that remove DPCs outside of S phase. Moreover, we highlight a recent paradigm shifting finding that indicates that DPCs are not always detrimental, but can also play a protective role, preserving the genome from more deleterious forms of DNA damage.

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Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Cited by 2 publications

References 103 publications

Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes

Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes

Mechanism of Type IA Topoisomerases

How to fix DNA-protein crosslinks

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