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      Untangling the roles of TOP2A and TOP2B in transcription and cancer

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      Author(s): 1 , * , , 1 , 2 , * ,
      Publication date (Electronic, pub):
      Journal: Science Advances
      Publisher: American Association for the Advancement of Science

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          Abstract

          Type II topoisomerases (TOP2) are conserved regulators of chromatin topology that catalyze reversible DNA double-strand breaks (DSBs) and are essential for maintaining genomic integrity in diverse dynamic processes such as transcription, replication, and cell division. While controlled TOP2-mediated DSBs are an elegant solution to topological constraints of DNA, DSBs also contribute to the emergence of chromosomal translocations and mutations that drive cancer. The central importance of TOP2 enzymes as frontline chemotherapeutic targets is well known; however, their precise biological functions and impact in cancer development are still poorly understood. In this review, we provide an updated overview of TOP2A and TOP2B in the regulation of chromatin topology and transcription, and discuss the recent discoveries linking TOP2 activities with cancer pathogenesis.

          Abstract

          Abstract

          From TADs to topoisomes, recent studies unfold the roles of TOP2A and TOP2B in genome regulation and carcinogenesis.

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          A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.

          Suhas Rao, Miriam H Huntley, Neva Durand … (2014)
          We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

            Erez Lieberman-Aiden, Nynke van Berkum, Louise Williams … (2009)
            We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.
            Article 0 comments Cited 1774 times – based on 0 reviews     Review now
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              • Record: found
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              Is Open Access

              COSMIC: the Catalogue Of Somatic Mutations In Cancer

              John G Tate, Sally Bamford, Harry C Jubb … (2018)
              Abstract COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC’s deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.
              Article 0 comments Cited 1606 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Liis Uusküla-Reimand:
                ORCID: https://orcid.org/0000-0002-5322-5524
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Michael D. Wilson:
                ORCID: https://orcid.org/0000-0002-4015-3066
                Role: Funding acquisitionRole: Writing - original draft
                Journal
                Journal ID (nlm-ta): Sci Adv
                Journal ID (iso-abbrev): Sci Adv
                Journal ID (publisher-id): sciadv
                Journal ID (hwp): advances
                Title: Science Advances
                Publisher: American Association for the Advancement of Science
                ISSN (Electronic): 2375-2548
                Publication date Collection: November 2022
                Publication date (Electronic, pub): 02 November 2022
                Volume: 8
                Issue: 44
                Electronic Location Identifier: eadd4920
                Affiliations
                [ 1 ]Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
                [ 2 ]Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
                Author notes
                [* ]Corresponding author. Email: liis.uuskula-reimand@ 123456sickkids.ca (L.U.-R.); michael.wilson@ 123456sickkids.ca (M.D.W.)
                Author information
                https://orcid.org/0000-0002-5322-5524
                https://orcid.org/0000-0002-4015-3066
                Article
                Publisher ID: add4920
                DOI: 10.1126/sciadv.add4920
                PMC ID: 9629710
                PubMed ID: 36322662
                SO-VID: 87c1a3fb-abd3-4574-93b2-0d8e785cc69f
                Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 15 June 2022
                Date accepted : 12 September 2022
                Funding
                Funded by: Cancer Research Society, Next Generation of Scientist Scholarship;
                Award ID: PIN25558
                Funded by: Tier II Canada Research Chair;
                Categories
                Subject: Review
                Subject: Biomedicine and Life Sciences
                Subject: SciAdv reviews
                Subject: Cancer
                Subject: Molecular Biology
                Subject: Molecular Biology
                Custom metadata
                Copyeditor Karla Peñamante

                Data availability:

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