Topoisomerases, chromatin and transcription termination

Durand-Dubief, Mickaël; Svensson, J. Peter; Persson, Jenna; Ekwall, Karl

doi:10.4161/trns.2.2.14411

Cited by 27 publications

(21 citation statements)

References 33 publications

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“…Topoisomerases are thought to facilitate transcription elongation by relaxing supercoils [37]. Consistent with this model, loss of Top1 in Schizosaccharomyces pombe results in the accumulation of Pol II in gene bodies [38], [39]. The parallels of Pol V- and Pol II-mediated transcription have recently been highlighted [40], and we propose that TOP1α promotes transcription elongation by Pol V as it does for Pol II.…”

Section: Discussionsupporting

confidence: 79%

DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis

et al. 2014

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RNA-directed DNA methylation (RdDM) and histone H3 lysine 9 dimethylation (H3K9me2) are related transcriptional silencing mechanisms that target transposable elements (TEs) and repeats to maintain genome stability in plants. RdDM is mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerases Pol IV and Pol V, respectively. Through a chemical genetics screen with a luciferase-based DNA methylation reporter, LUCL, we found that camptothecin, a compound with anti-cancer properties that targets DNA topoisomerase 1α (TOP1α) was able to de-repress LUCL by reducing its DNA methylation and H3K9me2 levels. Further studies with Arabidopsis top1α mutants showed that TOP1α silences endogenous RdDM loci by facilitating the production of Pol V-dependent long non-coding RNAs, AGONAUTE4 recruitment and H3K9me2 deposition at TEs and repeats. This study assigned a new role in epigenetic silencing to an enzyme that affects DNA topology.

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Section: Discussionsupporting

confidence: 79%

DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis

et al. 2014

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“…This data supports a role for topoisomerase I in transcription termination in these genes [20]. Alternatively, the increased number of reads beyond the annotated termination sites may result from the induction of alternative poly(A) sites following camptothecin treatment or stabilization of the RNA past the 3’-cleavage site.…”

Section: Resultssupporting

confidence: 68%

Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin

et al. 2013

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The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5’-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B), which are defective in transcription-coupled repair (TCR), showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons.

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“…S. pombe Top1 and Top2 have previously been implicated in various stages of transcription [30]–[31]. We investigated the genome-wide transcription levels in the top3-105 mutant by total RNA extraction, reverse transcription and hybridization to tiling microarrays.…”

Section: Resultsmentioning

confidence: 99%

“…Since DNA is wrapped around the histone core of nucleosomes in a left-handed negative direction, negative supercoiling of DNA favors nucleosome assembly while positive supercoiling of DNA favors nucleosome disassembly. In agreement, DNA topoisomerases have been implicated in the dynamics of canonical H3 nucleosomes in vitro and in vivo [28]–[31]. Eukaryotic topoisomerase III is a type 1A topoisomerase capable of relaxing negatively supercoiled DNA [32]–[33].…”

Section: Introductionmentioning

confidence: 99%

DNA Topoisomerase III Localizes to Centromeres and Affects Centromeric CENP-A Levels in Fission Yeast

et al. 2013

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Centromeres are specialized chromatin regions marked by the presence of nucleosomes containing the centromere-specific histone H3 variant CENP-A, which is essential for chromosome segregation. Assembly and disassembly of nucleosomes is intimately linked to DNA topology, and DNA topoisomerases have previously been implicated in the dynamics of canonical H3 nucleosomes. Here we show that Schizosaccharomyces pombe Top3 and its partner Rqh1 are involved in controlling the levels of CENP-ACnp1 at centromeres. Both top3 and rqh1 mutants display defects in chromosome segregation. Using chromatin immunoprecipitation and tiling microarrays, we show that Top3, unlike Top1 and Top2, is highly enriched at centromeric central domains, demonstrating that Top3 is the major topoisomerase in this region. Moreover, centromeric Top3 occupancy positively correlates with CENP-ACnp1 occupancy. Intriguingly, both top3 and rqh1 mutants display increased relative enrichment of CENP-ACnp1 at centromeric central domains. Thus, Top3 and Rqh1 normally limit the levels of CENP-ACnp1 in this region. This new role is independent of the established function of Top3 and Rqh1 in homologous recombination downstream of Rad51. Therefore, we hypothesize that the Top3-Rqh1 complex has an important role in controlling centromere DNA topology, which in turn affects the dynamics of CENP-ACnp1 nucleosomes.

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Topoisomerases, chromatin and transcription termination

Cited by 27 publications

References 33 publications

DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis

DNA Topoisomerase 1α Promotes Transcriptional Silencing of Transposable Elements through DNA Methylation and Histone Lysine 9 Dimethylation in Arabidopsis

Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin

DNA Topoisomerase III Localizes to Centromeres and Affects Centromeric CENP-A Levels in Fission Yeast

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