SUMO Regulation of Cellular Processes (eBook)

Preface 6
Contents 8
1: Introduction to Sumoylation 10
1.1 The Sumo Proteins 10
1.2 The Enzymology of Sumoylation 12
1.3 Sumoylation Functions 14
1.4 Conclusion 16
References 17
Part I: Molecular Functions 22
2: Roles of Sumoylation in mRNA Processing and Metabolism 23
2.1 A Brief Introduction to RNA Processing Events, Interconnections to Transcription and Export 23
2.2 RNA Processing Factors as Sumoylation Substrates 24
2.3 5? Capping 29
2.4 Splicing 29
2.5 3? End Processing 31
2.6 Transcription Termination 33
2.7 Sumoylation of hnRNPs 34
2.8 Extending the Role of Sumo to mRNA Export 35
2.9 Sumo and RNA Editing 36
2.10 Conclusions 36
References 36
3: SUMO and Chromatin Remodeling 42
3.1 Introduction 43
3.2 Histone Sumoylation 43
3.3 SUMO and Higher Order Chromatin Structure 45
3.4 Telomeres and Centromeres 46
3.5 SUMO-Dependent Recruitment of General Transcriptional Corepressors 48
3.6 SUMO-Dependent Modulation of General Coregulator Activity 50
3.7 The Role of SUMO E3 Ligases in Chromatin Remodelling 51
3.8 Global Analysis of Chromatin Modification by SUMO 52
References 53
4: Functions of SUMO in the Maintenance of Genome Stability 58
4.1 Introduction 59
4.2 Components of the SUMO Pathway 60
4.2.1 SUMO Proteins 60
4.2.2 SUMO Ligases 60
4.2.3 SUMO Proteases 61
4.2.4 SUMO-Targeted Ubiquitin Ligases 62
4.2.5 SUMO-Targeted Ubiquitin Proteases 64
4.3 SUMO Proteomics 65
4.4 Effects of SUMO on DNA Replication and Replication Stress 66
4.4.1 SUMO in Replication Initiation 66
4.4.2 SUMO at Replication Forks and in Replication Stress 67
4.5 Effects of SUMO on Homologous Recombination 68
4.5.1 MMS21-Dependent Sumoylation 69
4.5.2 Sumoylation of RPA 71
4.5.3 Sumoylation of RAD52 71
4.5.4 Sumoylation of PCNA 73
4.5.5 Sumoylation of SGS1/BLM 75
4.5.6 Sumoylation of Thymidine DNA Glycosylase in Base Excision Repair 76
4.6 SUMO in the Maintenance of Telomere Function 78
4.7 Sumoylation in Chromosome Topology 82
4.7.1 Sumoylation of Cohesin 82
4.7.2 Sumoylation of Topoisomerase II 83
4.8 Conclusion 84
References 85
5: Regulation of Cellular Processes by SUMO: Understudied Topics 95
5.1 Introduction 95
5.2 Examples of Well-Studied SUMO-Regulated Processes 96
5.2.1 Genome Stability 96
5.2.2 Cell Cycle Regulation 96
5.2.3 Transcription 97
5.3 Examples of Less-Studied SUMO-Regulated Processes 97
5.3.1 RNA Editing 97
5.3.2 snoRNA 97
5.3.3 mRNA Translation 97
5.3.4 Protein Folding 98
5.3.5 Lipogenesis 99
5.3.6 Cell Morphology 99
5.3.7 Autophagy 100
5.4 Conclusion 101
References 101
6: The Molecular Interface Between the SUMO and Ubiquitin Systems 104
6.1 DNA Checkpoints, DNA-Repair 104
6.2 Key Historical Discoveries in the Field 105
6.3 More Recent Key Discoveries in the Field 106
6.4 The Identification of RNF4 106
6.5 Cancer, DNA Damage, and the Best Known Substrate of RNF4 108
6.6 Additional Substrates and Molecular Functions of RNF4 109
6.7 Sumoylation, Ubiquitination, Nuclear Receptors, Bile Acid Homeostasis, Cholesterol Metabolism, and the Inflammatory Response 110
6.8 SUMO, Ubiquitin, Acetyl, Pregnane X Receptor, and Drug Metabolism 111
References 113
7: SUMO and Nucleocytoplasmic Transport 116
7.1 Introduction 116
7.2 Compartment-Specific Sumoylation 119
7.3 Regulation of Nuclear Transport by Sumoylation 121
7.3.1 SUMO-Dependent Inhibition of Nuclear Export 121
7.3.2 SUMO-Dependent Stimulation of Nuclear Export 123
7.3.3 Sumoylation and Nuclear Import 124
7.4 Control of the Nuclear Transport Machinery by Sumoylation 125
7.5 Nucleocytoplasmic Transport of SUMO-Specific Enzymes 126
7.6 Conclusion 127
References 128
8: Sumo Modification of Ion Channels 132
8.1 Introduction 132
8.2 Extranuclear Targets of Sumoylation 134
8.3 Sumoylation of Ion Channels 135
8.3.1 K2P1 136
8.3.2 Kv1.5 138
8.3.3 GluR6 140
8.4 Ion Chanels as Probes of Sumo Modification at the Plasma Membrane 141
8.5 Conclusions 144
References 145
9: The Roles of SUMO in Metabolic Regulation 147
9.1 Introduction: Functions of SUMO in Metabolism 148
9.2 SUMO and Transcriptional Regulation of Metabolic Pathways 149
9.2.1 SUMO and Master Regulation of Lipid Biosynthesis 149
9.2.2 SUMO and Metabolic Nuclear Receptors 151
9.3 SUMO in Familial Partial Lipodystrophy 151
9.4 Metabolic Adaptation to Cellular and Oxidative Stress 152
9.5 SUMO and Energy Metabolism 153
9.5.1 SUMO in Muscle Metabolism 153
9.5.2 SUMO in Insulin Synthesis and Secretion 157
9.5.3 SUMO in Glucose Transport and Metabolism 158
9.5.4 SUMO in Mitochondrial Biogenesis and Metabolic Disease 159
9.6 SUMO and Folate-Mediated One-Carbon Metabolism 160
9.7 Conclusions 163
References 163
Part II: Cell Growth Regulation 173
10: The SUMO Pathway in Mitosis 174
10.1 Introduction 174
10.2 The SUMO Pathway 175
10.3 Outcomes of SUMO Modification 175
10.4 The Role of SUMO in Mitotic Chromosome Structure 177
10.5 SUMO and Centromere/Kinetochore Organization 179
10.6 SUMO and Cytokinesis 182
10.7 Conclusions and Perspectives 183
References 184
11: Wrestling with Chromosomes: The Roles of SUMO During Meiosis 188
11.1 Introduction 188
11.2 Sumoylation 189
11.2.1 Sumoylation in Meiosis: A Phenotypic Survey 189
11.2.2 Targets of Sumoylation in Meiosis 191
11.3 Centromeric Heterochromatin and Sumoylation 192
11.4 Centromeric Coupling 193
11.5 SUMO-Mediated Regulation of SC Dynamics 194
11.5.1 ZIP1 and ZIP3: A SUMO Connection 194
11.6 Meiotic DSB Repair/Recombination 196
11.7 Conclusions 197
References 197
12: Sumoylation in Development and Differentiation 200
12.1 Introduction 201
12.2 The Reproductive System 202
12.2.1 Vuval Morphogenesis 202
12.2.2 Sperm Differentiation 202
12.2.3 Oocyte Maturation 204
12.3 Embryonic Development 205
12.4 Stem Cells 205
12.4.1 Embryonic Stem Cells 205
12.4.2 Post-natal Stem Cells 207
12.5 Tissue and Cellular Differentiation 208
12.5.1 Epithelial Tissue 208
12.5.2 Myocytes 209
12.5.3 Neuronal Cells 211
12.5.4 Hematopoietic Cells 212
12.6 Conclusions 213
References 213
13: The Role of Sumoylation in Senescence 218
13.1 Introduction 218
13.2 Sumoylation and Senescence 221
13.3 Cellular Senescence and P53 Sumoylation 221
13.4 Sumoylation, Senescence and the Retinoblastoma Protein 223
13.5 Role of PML and Sumoylation in the Regulation of Senescence 224
13.6 Telomere Maintenance and SUMO 225
13.7 Conclusions 226
References 226
14: Regulation of Plant Cellular and Organismal Development by SUMO 230
14.1 Introduction 231
14.2 Phenotypes Associated with SUMO Pathway Mutants 232
14.3 SUMO Functions in Physiological Adaptation and Stress Responses 234
14.4 Flowering Time 237
14.5 Hormone Signaling 237
14.6 Sumo and Light Signaling 240
14.7 Roles in Cell Division, Meristem Proliferation, Meiosis, and Gametophyte Development 242
14.8 SUMO and Chromosome Functions 243
References 246
15: SUMO in Drosophila Development 251
15.1 The SUMO Pathway 251
15.2 SUMO and Drosophila Development 253
15.2.1 Regulation of Signal Transduction by SUMO 253
15.2.1.1 Ras/MAPK Signaling 253
15.2.1.2 Dpp Signaling 254
15.2.1.3 Jun N-Terminal Kinase Signaling 254
15.2.2 Regulation by SUMO of Spatially Restricted Sequence-Specific Transcription Factors 255
15.2.2.1 Bicoid 255
15.2.2.2 Spalt 255
15.2.3 Regulation by SUMO of Co-repressors 256
15.2.3.1 The Polycomb Group Protein Scm 256
15.2.3.2 Groucho 257
15.3 Conclusion 257
References 257
Part III: Diseases 260
16: Sumoylation: Implications for Neurodegenerative Diseases 261
16.1 Introduction 262
16.2 Parkinson’s Disease 262
16.3 Alzheimer’s Disease 265
16.4 Polyglutamine Diseases 266
16.4.1 Huntington’s Disease 267
16.4.2 Denatorubro-Pallidoluysian Atrophy 267
16.4.3 Spinobulbar Muscular Atrophy 268
16.4.4 Spinocerebellar Ataxias 268
16.4.5 Neuronal Intranuclear Inclusion Disease 269
16.5 Cellular Stress 270
16.6 Amyotrophic Lateral Sclerosis 271
16.7 Ischemia 271
16.8 Sumoylation as a Potential Drug Target 273
16.9 Conclusions and Perspectives 275
References 277
17: Sumoylation and Its Contribution to Cancer 282
17.1 Introduction 282
17.2 Upstream Signals Regulating SUMO-Conjugation System in Cancer 283
17.3 Regulation of SUMO E2 Conjugating Enzyme, UBC9, in Cancer 285
17.4 Involvement of SUMO E3 Ligases in Cancer 286
17.5 Involvement of SUMO-­Specific Proteases in Cancer 286
17.6 Regulation of Sumoylation at the Substrate Level and Implications in Cancer 287
17.7 SUMO Modification of Oncogenes and Tumor Suppressors 287
17.8 Conclusions 292
References 292
18: Sumoylation Modulates the Susceptibility to Type 1 Diabetes 298
18.1 Introduction 299
18.2 Characterization of SUMO4 in T1D Susceptibility 300
18.3 Genetic Heterogeneity for SUMO4 in the European Caucasians 303
18.4 Validation of SUMO4 as a Novel T1D Susceptibility Gene 303
18.5 The Effect of M55V Supports SUMO4 in T1D Susceptibility 304
18.6 Stress-Dependent SUMO4 Functionality 306
18.7 SUMO4 Acts as a Negative Regulator for the NF?B Signaling Pathway 307
18.8 SUMO4 Regulates Cytokine-Initiated JAK/STAT Signalings 309
18.9 SUMO4 Modulates AP-1 Tanscriptional Activity 310
18.10 SUMO4 Wrestles with Intracellular Stress 311
18.11 Conclusions 313
References 313
19: Sumoylation in Craniofacial Disorders 322
19.1 Key Role for Sumo in Development 323
19.2 Sumo 1 Haploinsufficiency Causes Cleft Lip and/or Palate 323
19.3 Sumoylation Regulates Craniofacial Developmental Genes 325
19.4 Sumo in Developmental Pathways and Syndromes 328
19.5 Sumo, Stress, and CL/P 330
19.6 Conclusions 330
References 331
20: Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases 335
20.1 Introduction 336
20.2 Sumoylation in the Nucleus Regulates Endothelial Dysfunction and Atherosclerosis 337
20.2.1 Steady Laminar Flow vs. Disturbed Flow 337
20.2.2 Nuclear ERK5 Sumoylation and EC Dysfunction 338
20.2.3 Sumoylation Mediated p53 Nuclear Export Leads to EC Apoptosis 340
20.2.4 Nuclear Export of De-sumoylation Enzyme SENP2 and Its Effects on Nuclear ERK5 and p53 340
20.2.5 D-Flow and DNA Methylation in the Nucleus 343
20.2.6 Nuclear Inducible Camp Early Repressor (ICER) Is Regulated by ERK5-Sumoylation in Heart 346
20.3 Sumoylation of Potassium Channels at the Plasma Membrane 347
20.4 Sumoylation of Mitochondrial Proteins 349
20.4.1 Overview of Mitochondrial Fission and Fusion 349
20.4.2 The Roles of DRP1 Sumoylation in Mitochondrial Fission SUMO1 vs SUMO2/3
20.5 Conclusions 351
References 351
21: Viral Interplay with the Host Sumoylation System 357
21.1 Introduction 357
21.2 DNA Viruses 358
21.2.1 Parvoviruses 358
21.2.2 Papillomaviruses 361
21.2.3 Adenoviruses 363
21.2.4 Herpesviruses 366
21.2.4.1 Herpes Simplex Virus 366
21.2.4.2 Varicella-Zoster Virus 367
21.2.4.3 Cytomegalovirus 367
21.2.4.4 Human Herpesvirus 6 369
21.2.4.5 Epstein-Barr Virus 370
21.2.4.6 Kaposi’s Sarcoma-Associated Herpes Virus 372
21.2.5 Poxviruses 374
21.3 RNA Viruses 374
21.3.1 Retrovirus 374
21.3.2 Orthomyxovirus 375
21.3.3 Filovirus 376
21.3.4 Paramyxovirus 376
21.3.5 Rhabdovirus 377
21.3.6 Coronavirus 377
21.3.7 Flavivirus 377
21.3.8 Picornavirus 377
21.3.9 Reovirus 378
21.3.10 Deltavirus 378
21.4 Conclusion 378
References 379
22: Sumoylation as an Integral Mechanism in Bacterial Infection and Disease Progression 387
22.1 Introduction 388
22.1.1 Host-Microbe Interactions 388
22.1.2 Sumoylation Regulates Cellular Processes 389
22.2 Bacterial Pathogens and Sumoylation 391
22.2.1 Strategies Employed by Bacteria to Intercept/Exploit Host Sumoylation 391
22.2.1.1 Mimicry of Sumoylation Machinery Components 392
22.2.1.2 Alteration of Sumoylation of Specific Proteins 393
22.2.1.3 Sumoylation of Virulence Factors and Functional Alterations 394
22.2.1.4 Global Modulation of Host Sumoylation Levels 395
22.2.1.5 Listeria monocytogenes 395
22.2.1.6 Shigella flexneri 397
22.2.1.7 Salmonella enterica serovar Typhimurium 397
22.3 Host Cellular Processes Affected by Perturbation of Sumoylation 399
22.3.1 Sumoylation and Transcriptional Regulation 399
22.3.2 Sumoylation and Cellular Inflammatory Cascade in Bacterial Infection 399
22.3.3 Sumoylation and Modulation of Cellular Metabolism by Bacteria 401
22.4 Conclusions 402
References 402
Index 407