The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage

Wendorff, Timothy J.; Schmidt, Bryan H.; Heslop, Pauline; Austin, Caroline A.; Berger, James M.

doi:10.1016/j.jmb.2012.07.014

Cited by 196 publications

(213 citation statements)

References 94 publications

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“…2a (Stage 0), gyrase forms two chambers, with the top chamber open and the lower C chamber closed. When DNA enters the upper chamber (Stage 1), it is drawn to the floor, which bends DNA into a V shape caused by two 75°bends on opposing sides of the DNA cleavage site (Wendorff et al 2012). DNA bending orients the DNA arms so that they compete with GyrA CTD for DNA binding and formation of a chiral (+) loop on one pinwheel element.…”

Section: What Controls Supercoil Density?mentioning

confidence: 99%

Species-specific supercoil dynamics of the bacterial nucleoid

Higgins

2016

Biophys Rev

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Bacteria organize DNA into self-adherent conglomerates called nucleoids that are replicated, transcribed, and partitioned within the cytoplasm during growth and cell division. Three classes of proteins help condense nucleoids: (1) DNA gyrase generates diffusible negative supercoils that help compact DNA into a dynamic interwound and multiply branched structure; (2) RNA polymerase and abundant small basic nucleoid-associated proteins (NAPs) create constrained supercoils by binding, bending, and forming cooperative protein-DNA complexes; (3) a multi-protein DNA condensin organizes chromosome structure to assist sister chromosome segregation after replication. Most bacteria have four topoisomerases that participate in DNA dynamics during replication and transcription. Gyrase and topoisomerase I (Topo I) are intimately involved in transcription; Topo III and Topo IV play critical roles in decatenating and unknotting DNA during and immediately after replication. RNA polymerase generates positive (+) supercoils downstream and negative (−) supercoils upstream of highly transcribed operons. Supercoil levels vary under fast versus slow growth conditions, but what surprises many investigators is that it also varies significantly between different bacterial species. The MukFEB condensin is dispensable in the high supercoil density (σ) organism Escherichia coli but is essential in Salmonella spp. which has 15 % fewer supercoils. These observations raise two questions: (1) How do different species regulate supercoil density? (2) Why do closely related species evolve different optimal supercoil levels? Control of supercoil density in E. coli and Salmonella is largely determined by differences encoded within the gyrase subunits. Supercoil differences may arise to minimalize toxicity of mobile DNA elements in the genome.

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Section: What Controls Supercoil Density?mentioning

confidence: 99%

Species-specific supercoil dynamics of the bacterial nucleoid

Higgins

2016

Biophys Rev

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“…Accordingly, docking studies at other possible binding sites were performed, which revealed a binding domain close to etoposide binding site in the central domain of hTopoIIα (PDB ID: 4FM9). 24 However, these compounds are not hTopoIIα poisons like etoposide. 25 Hence, the interactions of these compounds are expected to be different from that of etoposide.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

Baviskar¹,

Amrutkar²,

Trivedi³

et al. 2015

ACS Med. Chem. Lett.

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A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choicebased change" in target-specific mode of action for rapid drug discovery.

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“…Topo II-α (9) is a commonly used proliferation marker that serves a function in DNA replication and chromosomal segregation by unwinding the DNA double helix. It is crucial for the active survival of cells and represents a common biomarker and target for multiple anticancer agents (30,31). Determination of Topo II-α expression facilitates the prognosis of overall survival rates of patients and their reaction to therapy (32).…”

Section: Discussionmentioning

confidence: 99%

Prediction of long‑term survival rates in patients undergoing curative resection for solitary hepatocellular carcinoma

et al. 2017

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Abstract. The present study developed a novel laboratory-based algorithm to predict long-term survival rates in patients undergoing curative resection for solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The present study included 426 patients with solitary HBV-related HCC who underwent surgery for primary tumors at a single center between 2003 and 2012. Demographic characteristics, laboratory analysis, clinical pathology and immunohistochemistry of topoisomerase II-a and Ki67 were analyzed. A simple prognostic risk calculator was developed using regression coefficients from multivariate models. A prognostic risk calculator incorporating tumor encapsulation, neutrophil-to-lymphocyte ratio, vascular invasion, α-fetoprotein level, Edmondson-Steiner classification, Topo II-α, prognostic nutritional index and Child-Pugh grade was constructed. The prognostic model demonstrated good discrimination with a C-index prior to adjustment of 0.81 (95% confidence interval: 0.78-0.84) and a bootstrap-corrected C-index of 0.81. Kaplan-Meier curves demonstrated that the probabilities of overall survival rates in the low-risk group were increased compared with those in the high-risk group. The areas under the receiver operating characteristic curve using the method were greater compared with those under the 7th Tumor-Node-Metastasis system and Cancer of the Liver Italian Program scoring system [0.83 vs. 0.62 and 0.77 (P<0.001), respectively]. The simple prognostic model of the present study accurately predicted survival rates in patients. Such a prognostic risk calculator for staging patients undergoing curative resection for solitary HBV-related HCC facilitates clinical surveillance and therapy.

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The Structure of DNA-Bound Human Topoisomerase II Alpha: Conformational Mechanisms for Coordinating Inter-Subunit Interactions with DNA Cleavage

Cited by 196 publications

References 94 publications

Species-specific supercoil dynamics of the bacterial nucleoid

Species-specific supercoil dynamics of the bacterial nucleoid

Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

Prediction of long‑term survival rates in patients undergoing curative resection for solitary hepatocellular carcinoma

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