Global Transcription Regulation by DNA Topoisomerase I in Exponentially Growing Saccharomyces cerevisiae Cells: Activation of Telomere-Proximal Genes by TOP1 Deletion

Lotito, Luca; Russo, Alessandra; Chillemi, Giovanni; Bueno, Susana; Cavalieri, Duccio; Capranico, Giovanni

doi:10.1016/j.jmb.2008.01.037

Cited by 35 publications

(34 citation statements)

References 35 publications

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“…S4). Our findings are consistent with previous reports that top1Δ affects only a small subset of telomere-proximal genes (32). We then examined the genome-wide binding of Pol II in a top1Δtop2-ts double mutant.…”

Section: Top2 Is Enriched At the Promoters Of Highly Transcribed Genessupporting

confidence: 91%

Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast

Sperling

Jeong

Kitada

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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DNA topoisomerases are believed to promote transcription by removing excessive DNA supercoils produced during elongation. However, it is unclear how topoisomerases in eukaryotes are recruited and function in the transcription pathway in the context of nucleosomes. To address this problem we present high-resolution genome-wide maps of one of the major eukaryotic topoisomerases, Topoisomerase II (Top2) and nucleosomes in the budding yeast, Saccharomyces cerevisiae. Our data indicate that at promoters Top2 binds primarily to DNA that is nucleosome-free. However, although nucleosome loss enables Top2 occupancy, the opposite is not the case and the loss of Top2 has little effect on nucleosome density. We also find that Top2 is involved in transcription. Not only is Top2 enriched at highly transcribed genes, but Top2 is required redundantly with Top1 for optimal recruitment of RNA polymerase II at their promoters. These findings and the examination of candidate-activated genes suggest that nucleosome loss induced by nucleosome remodeling factors during gene activation enables Top2 binding, which in turn acts redundantly with Top1 to enhance recruitment of RNA polymerase II.histone eviction | relaxase | gene regulation

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Section: Top2 Is Enriched At the Promoters Of Highly Transcribed Genessupporting

confidence: 91%

Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast

Sperling

Jeong

Kitada

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, RHPS4 could prevent telomerase to act on abruptly shortened telomeres due to camptothecindependent cleavage of the G strand. Alternatively, camptothecin could modify the general sensitivity of the cell to RHPS4, for example, by increasing its intracellular concentration or by modifying the expression program or even by blocking cells at a particular stage of the cell cycle (22).…”

Section: Discussionmentioning

confidence: 99%

G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors

Leonetti

Scarsella

Riggio

et al. 2008

Clinical Cancer Research

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Purpose: The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors. Experimental Design: The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice. Results: RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival. Conclusions: Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.

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“…A few studies, carried out in seeds, have, however, evidenced the correlation between telomere length and seed ageing (Boubriak et al, 2007). The relevance of the interaction between topo I and telomere DNA has been reported in yeast (Lotito et al, 2008); nevertheless, the possible effects of Tdp1 gene depletion on telomere homeostasis are still unknown, in animal as well in plant cells. In the present work, telomere shortening was demonstrated in the M. truncatula Tdp1α-depleted lines; this finding strongly suggests that the MtTdp1α function is necessary to resolve the stabilized topo I-DNA covalent complexes at the telomeric regions.…”

Section: -Test) (B)mentioning

confidence: 99%

“…Another intriguing aspect of Tdp1 function is related to the interaction between topo I and telomeric DNA. Kang et al (2004) showed that cell death induced by the topo I poison camptothecin is accompanied by DNA damage at telomeric repeats, while Lotito et al (2008) reported that topo I-defective S. cerevisiae cells are characterized by enhanced gene expression at the telomere proximal regions.…”

Section: Introductionmentioning

confidence: 99%

RNA-Seq analysis discloses early senescence and nucleolar dysfunction triggered by Tdp1α depletion in Medicago truncatula

Donà¹,

Confalonieri

Minio

et al. 2013

Journal of Experimental Botany

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An intron-spliced hairpin RNA approach was used for the targeted silencing of the MtTdp1α gene encoding the αisoform of tyrosyl-DNA phosphodiesterase 1 in Medicago truncatula Gaertn. Tyrosyl-DNA phosphodiesterase 1, involved in the repair of DNA topoisomerase I-mediated DNA damage, has been poorly investigated in plants. RNASeq analysis, carried out in the MtTdp1α-depleted plants, revealed different levels of transcriptional modulation (up-and down-regulation, alternative splicing, activation of alternative promoter) in genes involved in DNA damage sensing, DNA repair, and chromatin remodelling. It is suggested that the MtTdp1α gene has new, previously undetected roles in maintaining genome integrity. Up-regulation of senescence-associated genes and telomere shortening were observed. Moreover, impaired ribosome biogenesis indicated that the MtTdp1α gene is required for the nucleolar function. In agreement with the RNA-Seq data, transmission electron microscopy detected an altered nucleolar architecture in the MtTdp1α-depleted cells. Based on the reported data, a working hypothesis related to the occurrence of a nucleolar checkpoint in plant cells is proposed.

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Global Transcription Regulation by DNA Topoisomerase I in Exponentially Growing Saccharomyces cerevisiae Cells: Activation of Telomere-Proximal Genes by TOP1 Deletion

Cited by 35 publications

References 35 publications

Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast

Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast

G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors

RNA-Seq analysis discloses early senescence and nucleolar dysfunction triggered by Tdp1α depletion in Medicago truncatula

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