The Top1 paradox: Friend and foe of the eukaryotic genome

Kim, Nayun; Jinks-Robertson, Sue

doi:10.1016/j.dnarep.2017.06.005

Cited by 36 publications

(28 citation statements)

References 119 publications

(127 reference statements)

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“…Interestingly, elevated transcription levels have been shown to promote G4 formation that are favoured by negative superhelicity caused by the progression of RNA Pol complexes through DNA (57). In cells, topological stresses induced by RNA Pol II progression are mainly resolved by the TOP1 protein (73). In this study, we evidenced a major role of TOP1 protein in countering DNA breaks formation by CX5461 and PDS.…”

Section: Discussionmentioning

confidence: 52%

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

Pipier

Bossaert

Riou

et al. 2020

Preprint

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G-quadruplexes (G4), non-canonical DNA structures, are involved in several essential processes. Stabilization of G4 structures by small compounds (G4 ligands) affects almost all DNA transactions, including telomere maintenance and genomic stability. Here, thanks to a powerful and unbiased genetic approach, we identify topoisomerase 2-alpha (TOP2A) as the main effector of cell cytotoxicity induced by CX5461, a G4 ligand currently undergoing phase I/II clinical trials. This approach also allowed to identify new point mutations affecting TOP2A activity without compromising cell viability. Moreover, based on cross-resistance studies and siRNA-based protein depletion we report that TOP2A plays a major role in cell cytotoxicity induced by two unrelated clastogenic G4 ligands, CX5461 and pyridostatin (PDS). We also report that cytotoxic effects induced by both compounds are associated with topoisomerase 2mediated DNA breaks production. Finally, we show that TOP2-mediated DNA breaks production is strongly associated with RNA Pol II-dependent transcription and is countered by topoisomerase 1 (TOP1). Altogether our results indicate that clastogenic G4 ligands act as DNA structure-driven TOP2-poisons at transcribed regions bearing G-quadruplex structures.

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Section: Discussionmentioning

confidence: 52%

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

Pipier

Bossaert

Riou

et al. 2020

Preprint

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“…The TOP1 gene encodes a type IB topoisomerase that functions by nicking one strand of DNA and relieves both positive and negative supercoiling (Thrash et al, 1985; Wang, 2002). Also, Top1 has been implicated in maintaining genome stability during transcription (Brill and Sternglanz, 1988; Kim and Jinks-Robertson, 2011, 2017; Yadav et al, 2014). Therefore, the ZBE assay was performed in top1Δ mutants to determine if the increased topological tension caused an increase in DSBs at the fragile sequences.…”

Section: Resultsmentioning

confidence: 99%

AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile Zones

Pannunzio

Lieber

2017

Molecular Cell

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SUMMARY DNA double-strand breaks (DSBs) occurring within fragile zones of less than 200 base pairs account for the formation of the most common human chromosomal translocations in lymphoid malignancies, yet the mechanism of how breaks occur remains unknown. Here, we have transferred human fragile zones into S. cerevisiae in the context of a genetic assay to understand the mechanism leading to DSBs at these sites. Our findings indicate that a combination of factors is required to sensitize these regions. Foremost, DNA strand separation by transcription or increased torsional stress can expose these DNA regions to damage from either the expression of human AID or increased oxidative stress. This damage causes DNA lesions that, if not repaired quickly, are prone to nuclease cleavage resulting in DSBs. Our results provide mechanistic insight into why human neoplastic translocation fragile DNA sequences are more prone to enzymes or agents that cause longer-lived DNA lesions.

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“…Potential sources of the mutagenesis observed in topA mutants include the direct involvement of the enzyme, for example by the formation of a stable cleavage complex, or through a secondary mechanism linked to the accumulation of torsional strain due to the impaired activity of mutants. Extensive studies in yeast associated short sequence deletions within tandem repeats with the mutagenic processing of ribonucleotides by Topoisomerase I (Kim et al 2011;Huang, Ghosh, and Pommier 2015;Kim and Jinks-Robertson 2017) . In E. coli , disruption of topA leads to excessive negative supercoiling and the accumulation of RNA:DNA hybrid R-loops and the stabilization of non B-DNA forms (Drolet 2006) .…”

Section: Discussionmentioning

confidence: 99%

Point mutations in topoisomerase I alter the mutation spectrum in E. coli and impact the emergence of drug resistance genotypes

Bachar¹,

Itzhaki²,

Gleizer³

et al. 2019

Preprint

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Identifying the molecular mechanisms that give rise to genetic variation is essential for the understanding of evolutionary processes. Previously, we have used adaptive laboratory evolution to enable biomass synthesis from CO 2 in E. coli . Genetic analysis of adapted clones from two independently evolving populations revealed distinct enrichment for insertion and deletion mutational events. Here, we follow these observations to show that mutations in the gene encoding for DNA Topoisomerase 1 ( topA ) give rise to mutator phenotypes with characteristic mutational spectra. Using genetic assays and mutation accumulation lines, we show that point mutations in topA increase the rate of sequence deletion and duplication events. Interestingly, we observe that a single residue substitution (R168C) results in a high rate of head-to-tail (tandem) short sequence duplications, which are independent of existing sequence repeats. Finally, we show that the unique mutation spectrum of topA mutants enhances the emergence of antibiotic resistance in comparison to mismatch-repair ( mutS ) mutators, and lead to new resistance genotypes. Our findings highlight a potential link between the catalytic activity of topoisomerases and the fundamental question regarding the emergence of de novo tandem repeats, which are known modulators of bacterial evolution.

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The Top1 paradox: Friend and foe of the eukaryotic genome

Cited by 36 publications

References 119 publications

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

Transcription-associated topoisomerase activities control DNA-breaks production by G-quadruplex ligands

AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile Zones

Point mutations in topoisomerase I alter the mutation spectrum in E. coli and impact the emergence of drug resistance genotypes

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