Selection of DNA Cleavage Sites by Topoisomerase II Results from Enzyme-Induced Flexibility of DNA

Jang, Yunsu; Son, Hwa–Young; Lee, Sangwook; Hwang, Wonseok; Jung, Seung‐Ryoung; Byl, Jo Ann W.; Osheroff, Neil; Lee, Sang-Hwa

doi:10.1016/j.chembiol.2018.12.003

Cited by 15 publications

(18 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although limited in sample size, we observed a significant degree of correlation between the two times with a Pearson correlation of 0.74 (Figure 4(b)) and a 95% confidence interval of this correlation was estimated to be between 0.25 and 0.96 by bootstrap resampling (see Supplemental Material [21] for details). In line with our observation, six different DNA molecules studied recently by Jang et al [20] also show a strong correlation between hairband loop capture and release times. These findings suggest that cooperative kinking is a general mechanism that governs the kinetics of hairband loop capture and release.…”

supporting

confidence: 93%

“…Briefly, DNA molecules labeled with Cy3 and Cy5 near their sticky ends were immobilized to a NeutrAvidin-coated glass surface through a biotin linker. Such surface attachment scheme is expected to slightly lower the loop capture rate [19,20], but this effect is ir-relevant to the current study. Loop capture or release was triggered by exchange of buffers with different NaCl concentrations (see Supplemental Material [21] for more details).…”

mentioning

confidence: 79%

See 1 more Smart Citation

Base-Pair Mismatch Can Destabilize Small DNA Loops through Cooperative Kinking

Jeong

Kim

2019

Phys. Rev. Lett.

View full text Add to dashboard Cite

Base pair mismatch can relieve mechanical stress in highly strained DNA molecules, but how it affects their kinetic stability is not known. Using single-molecule Fluorescence Resonance Energy Transfer (FRET), we measured the lifetimes of tightly bent DNA loops with and without base pair mismatch. Surprisingly, for loops captured by stackable sticky ends which leave single-stranded DNA breaks (or nicks) upon annealing, the mismatch decreased the loop lifetime despite reducing the overall bending stress, and the decrease was largest when the mismatch was placed at the DNA midpoint. These findings suggest that base pair mismatch increases bending stress at the opposite side of the loop through an allosteric mechanism known as cooperative kinking. Based on this mechanism, we present a three-state model that explains the apparent dichotomy between thermodynamic and kinetic stability.

show abstract

supporting

confidence: 93%

mentioning

confidence: 79%

Base-Pair Mismatch Can Destabilize Small DNA Loops through Cooperative Kinking

Jeong

Kim

2019

Phys. Rev. Lett.

View full text Add to dashboard Cite

show abstract

“…In addition, the 3.6 Å structure of the DNA-binding/cleavage domain reveals a part of the CTD domain which was not previously observed and is positioned nearby the G-segment inflection points on each side of the enzyme. The curvature of the DNA was shown to be important for the selection of cleavage sites 41 . The particular localization of the CTD linker may structurally favor the curvature of the G-segment, stimulating DNA cleavage and favoring strand passage.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for allosteric regulation of Human Topoisomerase IIα

et al. 2021

View full text Add to dashboard Cite

The human type IIA topoisomerases (Top2) are essential enzymes that regulate DNA topology and chromosome organization. The Topo IIα isoform is a prime target for antineoplastic compounds used in cancer therapy that form ternary cleavage complexes with the DNA. Despite extensive studies, structural information on this large dimeric assembly is limited to the catalytic domains, hindering the exploration of allosteric mechanism governing the enzyme activities and the contribution of its non-conserved C-terminal domain (CTD). Herein we present cryo-EM structures of the entire human Topo IIα nucleoprotein complex in different conformations solved at subnanometer resolutions (3.6–7.4 Å). Our data unveils the molecular determinants that fine tune the allosteric connections between the ATPase domain and the DNA binding/cleavage domain. Strikingly, the reconstruction of the DNA-binding/cleavage domain uncovers a linker leading to the CTD, which plays a critical role in modulating the enzyme’s activities and opens perspective for the analysis of post-translational modifications.

show abstract

“…Besides, this minisatellite has a strand asymmetry in the G:C composition, which can contribute to the formation of the Z-form of DNA and lead to unequal recombination [34]. UPS29 has six Topo II recognition sites [35,36], two potential regions of DNA fracture (GTGCACACACACGTG), and several sites (GTGCACACACACACGGTG) with high MAR potential (0.8-1.0), which theoretically can bind to the dynamic ribonucleoprotein matrix of the nucleus [37]. Thus, the results of in silico analysis indicate a potential instability of this minisatellite ( Figure S1).…”

Section: Introductionmentioning

confidence: 99%

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

Сучкова

Borisova

Паткин

2020

IJMS

View full text Add to dashboard Cite

Epilepsy is a neurological disease with different clinical forms and inter-individuals heterogeneity, which may be associated with genetic and/or epigenetic polymorphisms of tandem-repeated noncoding DNA. These polymorphisms may serve as predictive biomarkers of various forms of epilepsy. ACAP3 is the protein regulating morphogenesis of neurons and neuronal migration and is an integral component of important signaling pathways. This study aimed to carry out an association analysis of the length polymorphism and DNA methylation of the UPS29 minisatellite of the ACAP3 gene in patients with epilepsy. We revealed an association of short UPS29 alleles with increased risk of development of symptomatic and cryptogenic epilepsy in women, and also with cerebrovascular pathologies, structural changes in the brain, neurological status, and the clinical pattern of seizures in both women and men. The increase of frequency of hypomethylated UPS29 alleles in men with symptomatic epilepsy, and in women with both symptomatic and cryptogenic epilepsy was observed. For patients with hypomethylated UPS29 alleles, we also observed structural changes in the brain, neurological status, and the clinical pattern of seizures. These associations had sex-specific nature similar to a genetic association. In contrast with length polymorphism epigenetic changes affected predominantly the long UPS29 allele. We suppose that genetic and epigenetic alterations UPS29 can modify ACAP3 expression and thereby affect the development and clinical course of epilepsy.

show abstract

Selection of DNA Cleavage Sites by Topoisomerase II Results from Enzyme-Induced Flexibility of DNA

Cited by 15 publications

References 58 publications

Base-Pair Mismatch Can Destabilize Small DNA Loops through Cooperative Kinking

Base-Pair Mismatch Can Destabilize Small DNA Loops through Cooperative Kinking

Structural basis for allosteric regulation of Human Topoisomerase IIα

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

Contact Info

Product

Resources

About