Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency

Álvarez-Quilón, Alejandro; Terrón-Bautista, José; Delgado‐Sainz, Irene; Serrano-Benítez, Almudena; Romero-Granados, Rocío; Martínez-García, Pedro Manuel; Jimeno-González, Silvia; Bernal‐Lozano, Cristina; Quintero, Cristina; García-Quintanilla, Lourdes; Cortés‐Ledesma, Felipe

doi:10.1038/s41467-020-14638-w

“…The DNA topoisomerases (topos) are critical enzymes involved in modulation of breaking and rejoining of DNA strand (Liu et al, 2020). There are two characteristic types of topos including DNA topoisomerase 1 (topo1) and DNA topoisomerase 2 (topo2) that have been shown to regulate chromosomal segregation and DNA replication, recombination and repair (Alvarez‐Quilon et al, 2020; Singh, Luxami, & Paul, 2020). Consequently, much attention has been directed towards targeting topos in cancer therapy to suppress growth and proliferation of cancer cells (Shu et al, 2020; Watanabe et al, 2020).…”

Section: Cryptotanshinone and Cancermentioning

confidence: 99%

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

Ashrafizadeh

¹

,

Zarrabi

²

,

Orouei

³

et al. 2020

Phytotherapy Research

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In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived‐natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well‐known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti‐inflammatory, anti‐diabetic and neuroprotective. Recently, studies have focused on anti‐tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti‐tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti‐tumor activity of chemotherapeutic agents, and elevating accumulation of anti‐tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti‐tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.

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“…To further test the predictive power of our approach, we generated genome wide predictions in mouse thymocytes and used TOP2B ChIP-seq data performed in our laboratory [ 60 ] to validate them. In order to test the specificity of our model, we evaluated the ChIP-seq signal generated by two different antibodies (Novus and Santa Cruz).…”

Section: Resultsmentioning

confidence: 99%

“…Upon etoposide treatment, abortive TOP2 activity results in DSBs at CTCF-RAD21 sites, as measured by the END-seq method [ 12 , 17 ]. Since TOP2-induced DSBs have important implications for cancer-linked translocations [ 12 , 17 , 18 , 60 , 61 ], we decided to test the capacity of our model to predict these breaks. Given that many of the datasets provided by Canela et al (2017) correspond to MEFs, we focused our analysis on this cell line and processed an END-seq sample treated with etoposide in addition to the already analyzed TOP2B ChIP-seq dataset (see S1 Table ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide prediction of topoisomerase IIβ binding by architectural factors and chromatin accessibility

Martínez-García

¹

,

García-Torres

²

,

Divina

³

et al. 2021

Self Cite

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DNA topoisomerase II-β (TOP2B) is fundamental to remove topological problems linked to DNA metabolism and 3D chromatin architecture, but its cut-and-reseal catalytic mechanism can accidentally cause DNA double-strand breaks (DSBs) that can seriously compromise genome integrity. Understanding the factors that determine the genome-wide distribution of TOP2B is therefore not only essential for a complete knowledge of genome dynamics and organization, but also for the implications of TOP2-induced DSBs in the origin of oncogenic translocations and other types of chromosomal rearrangements. Here, we conduct a machine-learning approach for the prediction of TOP2B binding using publicly available sequencing data. We achieve highly accurate predictions, with accessible chromatin and architectural factors being the most informative features. Strikingly, TOP2B is sufficiently explained by only three features: DNase I hypersensitivity, CTCF and cohesin binding, for which genome-wide data are widely available. Based on this, we develop a predictive model for TOP2B genome-wide binding that can be used across cell lines and species, and generate virtual probability tracks that accurately mirror experimental ChIP-seq data. Our results deepen our knowledge on how the accessibility and 3D organization of chromatin determine TOP2B function, and constitute a proof of principle regarding the in silico prediction of sequence-independent chromatin-binding factors.

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“…experimental TOP2B tracks in both organisms, showing that our model can be used to 48 generate virtual TOP2B signals in potentially any mammalian cell type and condition 49 for which sequencing data of CTCF, RAD21 and DNase I hypersensitivity are available. 50 Materials and methods 51 Processing publicly available data 52 The experimental data used in this study is summarized in S1 Table. When available, 53 we batch-downloaded mm9 and hg19 BAM files from ENCODE.…”

mentioning

confidence: 97%

“…The achieved predictions showed that the cross-cell type applications of the classifiers 398 did not decrease their performances, which acquired accurate predictions independently 399 of the training cell type ( Fig 4C; S4 Fig; Table 4). For example, when we applied NB 400 To further test the above observations, we used genome wide ChIP-seq TOP2B 405 binding in mouse thymocytes obtained in our laboratory [49] and assessed model 406 prediction accuracies on them. This time we generated models using a combination of 407 data from mouse liver, MEFs and activated B cells, which allowed us to better capture 408 the cell type specificities of TOP2B binding in a single classifier.…”

mentioning

confidence: 99%

Genome-wide prediction of topoisomerase IIβbinding by architectural factors and chromatin accessibility

Cortés‐Ledesma

¹

,

Martínez-García

²

,

García-Torres

³

et al. 2020

Preprint

Self Cite

0

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DNA topoisomerase II-β (TOP2B) is fundamental to remove topological problems linked to DNA metabolism and 3D chromatin architecture, but its cut-and-reseal catalytic mechanism can accidentally cause DNA double-strand breaks (DSBs) that can seriously compromise genome integrity. Understanding the factors that determine the genome-wide distribution of TOP2B is therefore not only essential for a complete knowledge of genome dynamics and organization, but also for the implications of TOP2-induced DSBs in the origin of oncogenic translocations and other types of chromosomal rearrangements. Here, we conduct a machine-learning approach for the prediction of TOP2B binding sites using publicly available sequencing data. We achieve highly accurate predictions, with accessible chromatin and architectural factors being the most informative features. Strikingly, TOP2B is sufficiently explained by only three features: DNase I hypersensitivity, CTCF and cohesin binding, for which genome-wide data are widely available. Based on this, we develop a predictive model for TOP2B genome-wide binding that can be used across cell lines and species, and generate virtual probability tracks that accurately mirror experimental ChIP-seq data. Our results deepen our knowledge on how the accessibility and 3D organization of chromatin determine TOP2B function, and constitute a proof of principle regarding the in silico prediction of sequence-independent chromatin-binding factors. Author summaryType II DNA topoisomerases (TOP2) are a double-edged sword. They solve topological problems in the form of supercoiling, knots and tangles that inevitably accompany genome metabolism, but they do so at the cost of transiently cleaving DNA, with the risk that this entails for genome integrity, and the serious consequences for human health, such as neurodegeneration, developmental disorders or predisposition to cancer. A comprehensive analysis of TOP2 distribution throughout the genome is therefore essential for a deep understanding of its function and regulation, and how this can affect genome dynamics and stability. Here, we use machine learning to thoroughly explore genome-wide binding of TOP2B, a vertebrate TOP2 paralog that has been linked to March 18, 2020 1/19 genome organization and cancer-associated translocations. Our analysis shows that TOP2B-DNA binding can be accurately predicted exclusively using information on DNA accessibility and binding of genome-architecture factors. We show that such information is enough to generate virtual maps of TOP2B binding along the genome, which we validate with de novo experimental data. Our results highlight the importance of TOP2B for accessibility and 3D organization of chromatin, and show that computationally predicted TOP2 maps can be accurately obtained using minimal publicly available datasets, opening the door for their use in different organisms, cell types and conditions with experimental and/or clinical relevance. Introduction 1 Type II DNA topoisomerases are unique in their ability to catalyze duplex ...

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Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency

Cited by 16 publications

References 49 publications

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

Genome-wide prediction of topoisomerase IIβ binding by architectural factors and chromatin accessibility

Genome-wide prediction of topoisomerase IIβbinding by architectural factors and chromatin accessibility

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