Laiho Molecular Determinants of Radiation Response

1. Auflage 2011
ISBN: 978-1-4419-8044-1
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 276 Seiten

Molecular Determinants of Radiation Response includes chapters by expert authors who detail the present understanding of key DNA damage response pathways and proteins. The chapters include comprehensive discussions on where and how specific alterations in function of these pathways and proteins result in substantive modifications of cellular response to DNA injury. Given the importance of therapies that induce DNA injury in the management of human disease, this book is timely and relevant for basic and translational researchers, as well as clinicians alike.

Autoren/Hrsg.

Laiho, Marikki

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;Contributors;12
4;Part I:Molecular Basis of the DNADamage Responses ;16
4.1;Chapter 1: H2AX in DNA Damage Response;17
4.1.1;1.1 Introduction;18
4.1.2;1.2 DSB Formation and H2AX Phosphorylation;18
4.1.2.1;1.2.1 Characteristics of .-H2AX Focal Formation and Removal;19
4.1.2.1.1;1.2.1.1 Size of .-H2AX Foci;19
4.1.2.1.2;1.2.1.2 DSB/.-H2AX Stoichiometry;22
4.1.2.1.3;1.2.1.3 Spatial Distribution of .-H2AX Foci;22
4.1.2.1.4;1.2.1.4 Temporal Distribution of .-H2AX Foci;23
4.1.2.1.5;1.2.1.5 Removal of .-H2AX Foci;24
4.1.2.1.6;1.2.1.6 Changes in .-H2AX Kinetics;24
4.1.2.2;1.2.2 .-H2AX Formation as an Essential Step in Biological Processes;25
4.1.2.2.1;1.2.2.1 Immune System Development;25
4.1.2.2.2;1.2.2.2 Male Fertility;25
4.1.2.3;1.2.3 .-H2AX Formation in Other Biological Processes;26
4.1.2.3.1;1.2.3.1 Telomere Dysfunction;26
4.1.2.3.2;1.2.3.2 Replication/Transcription;26
4.1.2.3.3;1.2.3.3 Virus Infection;26
4.1.2.3.4;1.2.3.4 Apoptosis;27
4.1.3;1.3 .-H2AX in DNA DSB Repair;27
4.1.3.1;1.3.1 .-H2AX and the Recruitment of DNA Repair and Chromatin Remodeling Factors;30
4.1.3.1.1;1.3.1.1 BRCA1-A Complex;30
4.1.3.1.2;1.3.1.2 53BP1;31
4.1.3.1.3;1.3.1.3 Chromatin Remodeling Complexes;31
4.1.3.1.4;1.3.1.4 Cohesins;32
4.1.3.2;1.3.2 .-H2AX and the Cell-Cycle Checkpoint;32
4.1.3.3;1.3.3 Complexity of Repair Foci Containing .-H2AX and Other Factors;33
4.1.4;1.4 .-H2AX as a Marker;34
4.1.4.1;1.4.1 Biological Processes;34
4.1.4.1.1;1.4.1.1 Cancer;34
4.1.4.1.2;1.4.1.2 Senescence;34
4.1.4.1.3;1.4.1.3 Radiation-Induced Bystander Effect;35
4.1.4.2;1.4.2 Clinical Applications;37
4.1.4.2.1;1.4.2.1 Biodosimetry and Individual Radiosensitivity;37
4.1.4.2.2;1.4.2.2 Chemotherapy;38
4.1.4.2.3;1.4.2.3 Environmental Toxins;39
4.1.5;1.5 Conclusions;40
4.1.6;References;40
4.2;Chapter 2: DNA Damage Signaling Downstream of ATM;48
4.2.1;2.1 Introduction;48
4.2.2;2.2 Ataxia-Telangiectasia and Rad3-Related;50
4.2.3;2.3 The Checkpoint Kinases;52
4.2.3.1;2.3.1 Chk1;53
4.2.3.2;2.3.2 Chk2;54
4.2.3.3;2.3.3 p38MAPK/MK2;55
4.2.4;2.4 Cooperation Between ATM and ATR;56
4.2.5;2.5 Mediators of the DNA Damage Response: BRCT-Containing Proteins;57
4.2.5.1;2.5.1 BRCA1;58
4.2.5.2;2.5.2 53BP1;58
4.2.5.3;2.5.3 MDC1/NFBD1;59
4.2.5.4;2.5.4 MCPH1/BRIT1;59
4.2.6;2.6 Activation of p53 by Upstream Kinases;59
4.2.7;2.7 Diverse Substrates of the Human PIKKs;60
4.2.8;References;61
4.3;Chapter 3: Checkpoint Control Following Radiation Exposure;66
4.3.1;3.1 Introduction;67
4.3.2;3.2 PIKK Activation and Signaling;67
4.3.2.1;3.2.1 ATM Activation;67
4.3.2.2;3.2.2 ATR Activation;69
4.3.2.3;3.2.3 Activation of ATM vs. ATR Following IR Exposure;70
4.3.2.4;3.2.4 Signaling from ATM/ATR to the Transducer Kinases;71
4.3.3;3.3 Cell Cycle Checkpoint Activation, Maintenance, and Adaptation;72
4.3.4;3.4 Mechanism Underlying DNA Damage-Induced G2/M Checkpoint Arrest;73
4.3.4.1;3.4.1 The Initiation of G2/M Checkpoint Arrest;74
4.3.4.2;3.4.2 The Maintenance of G2/M Checkpoint Arrest;76
4.3.4.3;3.4.3 Sensitivity of the G2/M Checkpoint;77
4.3.4.4;3.4.4 Role of Damage Response Mediator Proteins in G2/M Checkpoint Arrest;79
4.3.5;3.5 G1/S Arrest;80
4.3.5.1;3.5.1 p53 Dependent G1/S Arrest;80
4.3.5.2;3.5.2 A Second Process Inhibiting S Phase Entry After Radiation Exposure;81
4.3.5.3;3.5.3 Maintenance of G1/S Checkpoint Arrest;82
4.3.6;3.6 Intra-S-Phase Checkpoint Arrest;84
4.3.7;3.7 Significance of Cell Cycle Checkpoint Arrest;84
4.3.8;3.8 Conclusions;85
4.3.9;References;86
4.4;Chapter 4: Chromatin Responses to DNA Damage;91
4.4.1;4.1 Chromatin Remodeling is an Integral Component of the DNA Damage Response;91
4.4.2;4.2 The Chromatin Environment;92
4.4.2.1;4.2.1 Chromatin Remodeling Complexes and the Dynamic Nature of Chromatin;93
4.4.2.2;4.2.2 The INO80 Remodeling Complex;93
4.4.3;4.3 INO80 is Directly Involved in the DNA Damage Response;95
4.4.3.1;4.3.1 The INO80 Remodeling Complex Binds to Double Strand Breaks;95
4.4.3.2;4.3.2 INO80 Binding to Double Strand Breaks Depends on Histone H2AX Phosphorylation;96
4.4.3.3;4.3.3 INO80 is Involved in Homologous Recombination-Mediated DSB Repair;97
4.4.3.4;4.3.4 INO80 is Involved in the Early and Late Steps of Homologous Recombination;97
4.4.3.5;4.3.5 INO80 Can Evict Histones at DSBs;98
4.4.3.6;4.3.6 INO80 is Involved in the Recruitment of DNA Repair Factors to DSBs;99
4.4.4;4.4 INO80 is Phosphorylated at the Ies4 Subunit;100
4.4.5;4.5 INO80 is Important for Telomere Maintenance;102
4.4.6;4.6 INO80 is Involved in the DNA Damage Tolerance Pathways;103
4.4.6.1;4.6.1 The DNA Damage Response During Replication;103
4.4.6.2;4.6.2 Chromatin Remodeling at the Onset of DNA Replication;104
4.4.6.3;4.6.3 A Direct Role for INO80 During DNA Replication;105
4.4.6.3.1;4.6.3.1 INO80 Binds to Origins of Replication During S Phase;105
4.4.6.3.2;4.6.3.2 INO80 and the S Phase Checkpoint;105
4.4.6.3.3;4.6.3.3 INO80 and the DNA Damage Tolerance Pathways;106
4.4.6.3.4;4.6.3.4 INO80 Chromatin Remodeling Activity is Required for Efficient PCNA Ubiquitylation;107
4.4.6.3.5;4.6.3.5 INO80 is Required for the Formation of Rad51-Dependent Recombination Intermediates Induced by MMS Treatment;107
4.4.7;4.7 Conclusions and Perspectives;109
4.4.8;References;110
4.5;Chapter 5: Caenorhabditis elegans Radiation Responses;113
4.5.1;5.1 Introduction;113
4.5.2;5.2 The C. elegans Life Cycle and Implications for Radiation Responses;114
4.5.3;5.3 The C. elegans as an Experimental System;116
4.5.4;5.4 Basic Phenotypes Associated with DSB Repair and DNA Damage-Signalling Defects;117
4.5.5;5.5 C. elegans DNA Damage Response Signalling;121
4.5.6;5.6 C. elegans DSB Repair;123
4.5.7;5.7 Divergence Between Vertebrates and Nematodes;125
4.5.8;5.8 Telomere Replication and Mortal Germline Mutations;126
4.5.9;5.9 The Regulation of DNA Damage-Induced Germ Cell Apoptosis;127
4.5.10;References;130
5;Part II:Modulation of Radiation Responses:Opportunities for TherapeuticExploitation ;136
5.1;Chapter 6: Hypoxia and Modulation of Cellular Radiation Response;137
5.1.1;6.1 Characteristics of the Tumor Microenvironment;137
5.1.2;6.2 Hypoxic Induction of a Unique DNA Damage Response;140
5.1.3;6.3 Hypoxic Inhibition of DNA Repair Pathways;143
5.1.4;6.4 Exploitation of the Hypoxic Environment;145
5.1.5;6.5 Conclusion;146
5.1.6;References;147
5.2;Chapter 7: Inhibitors of DNA Repair and Response to Ionising Radiation;152
5.2.1;7.1 Introduction;153
5.2.2;7.2 The Role of Different DNA Repair Pathways for IR-Induced DNA Lesions;153
5.2.2.1;7.2.1 Non-homologous End Joining;154
5.2.2.2;7.2.2 Homologous Recombination;156
5.2.2.2.1;7.2.2.1 Homologous Recombination is Regulated by Checkpoint and Cyclin Dependent Kinases;158
5.2.2.3;7.2.3 Other DNA Repair Pathways Repairing IR-Induced Damage;158
5.2.3;7.3 Targeting Main DNA Repair Pathways in Combination with IR as a Therapeutic Strategy;160
5.2.4;7.4 Exploiting DNA Repair Defects for Selective Cancer Therapy;167
5.2.5;7.5 Conclusions;171
5.2.6;References;172
5.3;Chapter 8: Gene Therapy and Radiation;181
5.3.1;8.1 Introduction;181
5.3.2;8.2 Gene Therapy Strategies That Have Been Combined with Radiation Therapy in the Clinic;182
5.3.2.1;8.2.1 Suicide Gene Therapy;182
5.3.2.2;8.2.2 p53 Gene Therapy;184
5.3.2.3;8.2.3 Tumor Necrosis Factor Alpha (TNFa) Gene Therapy;185
5.3.3;8.3 Gene Therapy Strategies That Have Been Combined with Radiation in Preclinical Models;186
5.3.3.1;8.3.1 Replication-Competent Oncolytic Adenoviruses;186
5.3.3.2;8.3.2 Targeting Signal Transduction and Apoptotic Pathways;187
5.3.3.3;8.3.3 Targeting DNA Repair Pathways;187
5.3.3.4;8.3.4 Other Strategies;188
5.3.4;8.4 Conclusion;188
5.3.5;References;189
5.4;Chapter 9: Molecular Targeted Drug Delivery Radiotherapy;195
5.4.1;9.1 Introduction;195
5.4.2;9.2 Role of Vasculature in Development and Treatment of Solid Tumors;196
5.4.3;9.3 Radiation-Induced Prosurvival Signal Transduction Pathways;196
5.4.3.1;9.3.1 PI3K/Akt Pathway;198
5.4.3.2;9.3.2 MAPK/ERK Pathway;199
5.4.3.3;9.3.3 Phospholipids and Cytosolic Phospholipase A2 (cPLA2);199
5.4.3.4;9.3.4 Signaling by the cPLA2 Products LPC and LPA;201
5.4.4;9.4 Summary;204
5.4.5;References;204
5.5;Chapter 10: EGFR Signaling and Radiation;209
5.5.1;10.1 EGFR Biology;210
5.5.2;10.2 EGFR Signaling and Effect on Radiation Response;210
5.5.2.1;10.2.1 EGFR and Tumor Cell Repopulation Following Radiation;211
5.5.2.2;10.2.2 EGFR and DNA Damage Repair;211
5.5.2.3;10.2.3 EGFR Inhibitors;212
5.5.2.4;10.2.4 Anti-EGFR mAbs;214
5.5.2.5;10.2.5 Anti-EGFR TKIs;216
5.5.3;10.3 Combination of EGFR Targeting Agents with Radiation;218
5.5.4;10.4 Clinical Trials Combining EGFR Inhibitors and Radiation;221
5.5.4.1;10.4.1 Toxicities of Anti-EGFR mAbs and TKIs;224
5.5.5;10.5 Resistance to EGFR Inhibitors;225
5.5.5.1;10.5.1 Genetic Mutations and Resistance;225
5.5.5.2;10.5.2 Tyrosine Kinase Receptors and Resistance;226
5.5.5.3;10.5.3 Nuclear EGFR and Resistance;227
5.5.6;10.6 Conclusions;227
5.5.7;References;228
5.6;Chapter 11: Thermal Modulation of Radiation-Induced DNA Damage Responses;235
5.6.1;11.1 Introduction;236
5.6.2;11.2 Evidence that Heat Effects on Proteins Involvedor Impacting DNA Repair Pathways are Responsiblefor Radiosensitization;238
5.6.3;11.3 Perturbation of Proteins Known to Participate in DNA Repair Signaling Pathways;240
5.6.3.1;11.3.1 Hyperthermia Effects on the MRN Complex;240
5.6.3.2;11.3.2 Hyperthermia Effects Involving .-H2AX;243
5.6.3.3;11.3.3 Hyperthermia Effects on 53BP1;244
5.6.4;11.4 Masking of DNA Damage by Proteins Normally Not Associated with DNA Repair;247
5.6.4.1;11.4.1 Evidence from Neutral Comet Studies;248
5.6.4.2;11.4.2 Evidence from DNA Supercoiling Studies (Halo Assay);249
5.6.4.3;11.4.3 Evidence that Masking of DNA Damage Increases Sensitivity to Ionizing Radiation;249
5.6.5;11.5 Summary of the Radiosensitization Resulting from KeyInteractions Between the Proteotoxic and DNA DamageStress Responses;251
5.6.6;11.6 Nuclear and Chromatin Structure;251
5.6.7;11.7 Targeting the Intersection of the Proteotoxic and DNADamage Stress Response Pathways to Improve the TERat Clinically Achievable Temperatures;252
5.6.8;References;253
5.7;Chapter 12: Radiation-Induced Immune Modulation;258
5.7.1;12.1 The Abscopal Effect;258
5.7.1.1;12.1.1 Immunological Mechanisms Underlying the Abscopal Effect;259
5.7.1.2;12.1.2 Nonimmunological Mechanisms Underlying the Abscopal Effect;260
5.7.1.3;12.1.3 Counterpoint: Acceleration of Metastatic Disease by Local Irradiation;260
5.7.2;12.2 Local Immunological Effects of Radiation;261
5.7.2.1;12.2.1 Effects of Radiation on Tumor Cells;261
5.7.2.2;12.2.2 Effects on the Tumor-Associated Vasculature;262
5.7.2.3;12.2.3 Effects on Local Immune Cells;263
5.7.3;12.3 Systemic Immunological Effects of Radiation;263
5.7.3.1;12.3.1 Effects of Radiation on Cytokine Levels;264
5.7.3.2;12.3.2 Effects on Tumor Burden;265
5.7.3.3;12.3.3 Mechanisms Underlying Immune Stimulatory Effects of Radiation;265
5.7.4;12.4 Evidence for Immunological Effects of Radiotherapy in Humans;266
5.7.5;12.5 Clinical Studies Combining Immunotherapy with Radiotherapy;267
5.7.6;12.6 Conclusion;268
5.7.7;References;268
6;Index;271