Abstract
The human genome contains a unique class of domains, referred to as AT islands, which consist typically of 200-1000 bp long tracts of up to 100% A / T DNA. The significance of AT islands as potential targets for chemotherapeutic intervention stems from two main aspects. First, AT islands are inherently unstable (expandable) minisatellites that are found in various known loci of genomic instability, such as ATrich fragile sites. Second, AT islands are involved in the organization of the genomic DNA on the nuclear matrix by acting as scaffold / matrix attachment regions, S / MARs. DNA duplexes of AT islands are unusually flexible and prone to base unpairing, which are crucial MAR attributes. Various AT islands show high binding affinity for isolated nuclear matrices and associate with the nuclear matrix in the cell. The cellular MAR function of AT islands may differ in cancer and normal cells. The abnormally expanded AT islands in the FRA16B fragile site in leukemic CEM cells act as strong, permanent MARs, while their unexpanded counterparts in normal cells are loop localized. Given their instability and involvement in the remodeling of the nuclear architecture, AT islands may be a factor in cancerous phenotypes. AT islands are preferentially targeted by the extremely potent DNA-alkylating antitumor drugs, bizelesin and U78779. High lethality of lesions in AT islands is consistent with the critical role of MAR domains in DNA replication. The abnormal structure / function of AT islands, such as their expansion and acquired strong MAR properties, may sensitize cancer cells to AT island targeting drugs.
Keywords: at islands, genomic instability, at-rich, fragile sites, mar domains, dna replication, bizelesin
Current Cancer Drug Targets
Title: AT Islands - Their Nature and Potential for Anticancer Strategies
Volume: 4 Issue: 2
Author(s): Jan M. Woynarowski
Affiliation:
Keywords: at islands, genomic instability, at-rich, fragile sites, mar domains, dna replication, bizelesin
Abstract: The human genome contains a unique class of domains, referred to as AT islands, which consist typically of 200-1000 bp long tracts of up to 100% A / T DNA. The significance of AT islands as potential targets for chemotherapeutic intervention stems from two main aspects. First, AT islands are inherently unstable (expandable) minisatellites that are found in various known loci of genomic instability, such as ATrich fragile sites. Second, AT islands are involved in the organization of the genomic DNA on the nuclear matrix by acting as scaffold / matrix attachment regions, S / MARs. DNA duplexes of AT islands are unusually flexible and prone to base unpairing, which are crucial MAR attributes. Various AT islands show high binding affinity for isolated nuclear matrices and associate with the nuclear matrix in the cell. The cellular MAR function of AT islands may differ in cancer and normal cells. The abnormally expanded AT islands in the FRA16B fragile site in leukemic CEM cells act as strong, permanent MARs, while their unexpanded counterparts in normal cells are loop localized. Given their instability and involvement in the remodeling of the nuclear architecture, AT islands may be a factor in cancerous phenotypes. AT islands are preferentially targeted by the extremely potent DNA-alkylating antitumor drugs, bizelesin and U78779. High lethality of lesions in AT islands is consistent with the critical role of MAR domains in DNA replication. The abnormal structure / function of AT islands, such as their expansion and acquired strong MAR properties, may sensitize cancer cells to AT island targeting drugs.
Export Options
About this article
Cite this article as:
Woynarowski M. Jan, AT Islands - Their Nature and Potential for Anticancer Strategies, Current Cancer Drug Targets 2004; 4 (2) . https://dx.doi.org/10.2174/1568009043481524
DOI https://dx.doi.org/10.2174/1568009043481524 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Nano Conjugated PLGA-Chlorambucil: Synthesis In Vitro Anti Non- Hodgkin's Lymphoma Cellular Assay
Letters in Drug Design & Discovery Anesthesia for Bronchoscopy
Current Pharmaceutical Design S1P Regulation of Macrophage Functions in the Context of Cancer
Anti-Cancer Agents in Medicinal Chemistry NF-κ B and Rheumatic Diseases
Endocrine, Metabolic & Immune Disorders - Drug Targets Angiogenesis and Angiogenesis Inhibitors: a New Potential Anticancer Therapeutic Strategy
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Recent Advances in T Cell Adoptive Immunotherapy of Cancer
Current Cancer Therapy Reviews Cytokines as Anti-Angiogenic Agents in Haematological Malignancies
Current Cancer Drug Targets Cyclotron Production of PET Radiometals in Liquid Targets: Aspects and Prospects
Current Radiopharmaceuticals Breaking the Barrier of Cancer Through Liposome Loaded with Phytochemicals
Current Drug Delivery Development of Novel, Highly Cytotoxic Fusion Constructs Containing Granzyme B: Unique Mechanisms and Functions
Current Pharmaceutical Design CD4+ T Cell Responses in the Immune Control Against Latent Infection by Epstein-Barr Virus
Current Molecular Medicine Monoclonal Antobodies: Application in Radiopharmacy
Current Radiopharmaceuticals Anticancer Potential of Dietary Natural Products: A Comprehensive Review
Anti-Cancer Agents in Medicinal Chemistry Lymphoproliferative Lesions in IgG4-Related Disease
Current Immunology Reviews (Discontinued) Immunotoxins in the Treatment of Hematologic Malignancies
Current Drug Targets Enhancement in Biological Activity of L-Asparginase by its Conjugation on Silica Nanoparticles
Recent Patents on Nanotechnology Paraneoplastic Neurological Syndromes - Diagnosis and Management
Current Pharmaceutical Design An Expanding Appreciation of the Role Chemokine Receptors Play in Cancer Progression
Current Pharmaceutical Design Overcoming Drug Resistance by Enhancing Apoptosis of Tumor Cells
Current Cancer Drug Targets Radiation-Induced Extracranial Carotid Stenosis
Vascular Disease Prevention (Discontinued)