Abstract
Exposure to ionizing radiation (IR) results in the formation of DNA double strand breaks, resulting in the activation of phosphatidylinositol 3-kinase-like kinases ATM, ATR and DNK-PKcs. A physiologically important downstream target is the minor histone H2A variant, H2AX, which is rapidly phosphorylated on Ser 139 of the carboxyl tail after IR. Recent work suggests that phosphorylated H2AX (γ-H2AX) plays an important role in the recruitment and/or retention of DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 and 53BP1. H2AX-/- mouse embryonic fibroblasts are radiation sensitive and demonstrate deficits in repairing DNA damage compared to their wildtype counterparts. Cells treated with peptide inhibitors of γ-H2AX demonstrate increased radiosensitivity following radiation compared with untreated irradiated cells. Analysis of the kinetics of γ-H2AX clearance after IR or other DNA damaging agents reveals a correlation between increased γ-H2AX persistence and unrepaired DNA damage and cell death. These data highlight the potential of post-translational modifications of chromatin as a therapeutic target for enhancing the efficacy of radiotherapy. Therapies that either block γ-H2AX foci formation by inhibiting upstream kinase activity or that directly inhibit H2AX function may interfere with DNA damage repair processes and warrant further investigation as potential radiosensitizing agents. Agents that increase persistence of γ-H2AX after IR are likely to increase unrepaired DNA damage.
Keywords: H2AX, radiation, radiosensitizers, DNA damage, cancer
Current Cancer Drug Targets
Title: γ-H2AX as a Therapeutic Target for Improving the Efficacy of Radiation Therapy
Volume: 6 Issue: 3
Author(s): J. Kao, M. T. Milano, A. Javaheri, M. C. Garofalo, S. J. Chmura, R. R. Weichselbaum and S. J. Kron
Affiliation:
Keywords: H2AX, radiation, radiosensitizers, DNA damage, cancer
Abstract: Exposure to ionizing radiation (IR) results in the formation of DNA double strand breaks, resulting in the activation of phosphatidylinositol 3-kinase-like kinases ATM, ATR and DNK-PKcs. A physiologically important downstream target is the minor histone H2A variant, H2AX, which is rapidly phosphorylated on Ser 139 of the carboxyl tail after IR. Recent work suggests that phosphorylated H2AX (γ-H2AX) plays an important role in the recruitment and/or retention of DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 and 53BP1. H2AX-/- mouse embryonic fibroblasts are radiation sensitive and demonstrate deficits in repairing DNA damage compared to their wildtype counterparts. Cells treated with peptide inhibitors of γ-H2AX demonstrate increased radiosensitivity following radiation compared with untreated irradiated cells. Analysis of the kinetics of γ-H2AX clearance after IR or other DNA damaging agents reveals a correlation between increased γ-H2AX persistence and unrepaired DNA damage and cell death. These data highlight the potential of post-translational modifications of chromatin as a therapeutic target for enhancing the efficacy of radiotherapy. Therapies that either block γ-H2AX foci formation by inhibiting upstream kinase activity or that directly inhibit H2AX function may interfere with DNA damage repair processes and warrant further investigation as potential radiosensitizing agents. Agents that increase persistence of γ-H2AX after IR are likely to increase unrepaired DNA damage.
Export Options
About this article
Cite this article as:
Kao J., Milano T. M., Javaheri A., Garofalo C. M., Chmura J. S., Weichselbaum R. R. and Kron J. S., γ-H2AX as a Therapeutic Target for Improving the Efficacy of Radiation Therapy, Current Cancer Drug Targets 2006; 6 (3) . https://dx.doi.org/10.2174/156800906776842957
DOI https://dx.doi.org/10.2174/156800906776842957 |
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
-
Biomarkers to Assess the Targeting of DNA Repair Pathways to Augment Tumor Response to Therapy
Current Molecular Medicine Microgravity Alters Cancer Growth and Progression
Current Cancer Drug Targets HPV Vaccination in Adolescents: From Clinical Data to Implementation and Practice
Current Cancer Therapy Reviews DoE Based Optimization and Development of Spray-Dried Chitosan-Coated Alginate Microparticles Loaded with Cisplatin for the Treatment of Cervical Cancer
Current Molecular Pharmacology Life and Death of Nerve Cells: Therapeutic Cytokine Signaling Pathways
Current Signal Transduction Therapy Heparan Sulphate Proteoglycans and Viral Vectors : Ally or Foe?
Current Gene Therapy Histone Modifications as Molecular Targets in Nasopharyngeal Cancer
Current Medicinal Chemistry Polymeric Nanoparticles to Combat Squamous Cell Carcinomas in Patients with Dystrophic Epidermolysis Bullosa
Recent Patents on Nanomedicine Anti-Epidermal Growth Factor Receptor Antibodies in the Treatment of Metastatic Colorectal Cancer
Recent Patents on Anti-Cancer Drug Discovery Erlotinib: A Targeted Anticancer Drug
Current Cancer Therapy Reviews Anticancer Effect of Amygdalin (Vitamin B-17) on Hepatocellular Carcinoma Cell Line (HepG2) in the Presence and Absence of Zinc
Anti-Cancer Agents in Medicinal Chemistry Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs
MicroRNA Multimodality Imaging of RNA Interference
Current Medicinal Chemistry Cannabinoid System as a Potential Target for Drug Development in the Treatment of Cardiovascular Disease
Current Vascular Pharmacology Engineered Nanoparticles Against MDR in Cancer: The State of the Art and its Prospective
Current Pharmaceutical Design EBV-Related Malignancies, Outcomes and Novel Prevention Strategies
Infectious Disorders - Drug Targets Cancer-associated Autoantibodies as Biomarkers for Early Detection and Prognosis is Cancer: An Update
Current Cancer Therapy Reviews Targeting Transcription Factors for Cancer Therapy
Current Pharmaceutical Design Alpha-1 Antitrypsin: It’s Role in Health and Disease
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Natural DNA Intercalators as Promising Therapeutics for Cancer and Infectious Diseases
Current Cancer Drug Targets