DNA Repair Disorders

Preface
Contents
Chapter 1: Molecular Mechanism of DNA Damage Recognition for Global Genomic Nucleotide Excision Repair: A Defense System Against UV-Induced Skin Cancer
	1.1 Introduction
	1.2 Mammalian NER Pathways
		1.2.1 Lesion Recognition
		1.2.2 Lesion Verification and Demarcation
		1.2.3 Dual Incisions
		1.2.4 DNA Repair Synthesis and Ligation
	1.3 XPC Recognizes a Broad Range of Substrates for NER
		1.3.1 Architecture of the XPC Complex
		1.3.2 XPC Indirectly Senses DNA Lesions
	1.4 TFIIH and XPA Ensure Fidelity of GG-NER
		1.4.1 Two-Step Damage Recognition and TFIIH ATPases/Helicases
		1.4.2 XPA Supports the Lesion Recognition Functions of TFIIH
	1.5 UV-DDB as a Suppressor of UV-Induced Mutagenesis and Carcinogenesis
		1.5.1 UV-DDB Assists XPC in Recognizing UV-Induced Photolesions
		1.5.2 UV-DDB and Cellular DNA Damage Responses
	1.6 Roles of Chromatin Structures in Regulation of Lesion Recognition
	1.7 Conclusions
	References
Chapter 2: Disorders with Deficiency in TC-NER: Molecular Pathogenesis of Cockayne Syndrome and UV-Sensitive Syndrome
	2.1 Introduction
	2.2 Transcription-Coupled Nucleotide Excision Repair
		2.2.1 Molecular Mechanism of TC-NER
		2.2.2 TC-NER-Deficient Disorders
		2.2.3 Diagnostic Methods for TC-NER-Deficient Disorders
	2.3 Molecular Pathogenesis of Cockayne Syndrome and UV-Sensitive Syndrome
		2.3.1 Proteins Involved in the Initiation Step of TC-NER
			2.3.1.1 CSA and CSB
			2.3.1.2 UVSSA and USP7
			2.3.1.3 General Model of the TC-NER Initiation Process
		2.3.2 Molecular Pathogenesis of CS and UVSS
			2.3.2.1 Model 1: The Role of CS Proteins in Oxidative DNA Damage Repair
			2.3.2.2 Model 2: The Role of CSB in Basal Transcription
			2.3.2.3 Model 3: The Role of TC-NER in the Processing of Stalled RNA Pol IIo
	2.4 Concluding Remarks and Future Prospect
	References
Chapter 3: Neurological Symptoms in Xeroderma Pigmentosum
	3.1 The Neurological Manifestations and Natural History of X-PA
	3.2 MRI Findings
	3.3 Peripheral Neuropathy
	3.4 Neuropathological Findings in Autopsy Cases
	3.5 The Cause of Neurological Complications in XP-A
	References
Chapter 4: Hearing Impairment in Xeroderma Pigmentosum: Animal Models and Human Studies
	4.1 Introduction
		4.1.1 Clinical Features of Hearing in Patients with XP
		4.1.2 Severe Hearing Impairment in Patients with XP
	4.2 Audiological Tests
		4.2.1 Pure-Tone Audiometry
		4.2.2 Auditory Brainstem Response (ABR)
		4.2.3 Otoacoustic Emissions (OAE)
	4.3 Histopathology of the Inner Ear in Patients with XP
	4.4 Animal Studies
		4.4.1 Hearing in Xpa–Deficient Mice
		4.4.2 Morphological Features of Xpa-Deficient Mice Cochleae
	4.5 Molecular Mechanism of Hearing Loss in XP
	4.6 Patient Hearing Care
	References
Chapter 5: Epidemiological Study of Xeroderma Pigmentosum in Japan: Genotype-Phenotype Relationship
	5.1 Introduction
	5.2 Epidemiology
	5.3 Cutaneous Symptoms of XP
	5.4 Neurological Symptom of XP
	5.5 Eye Manifestation of XP
	5.6 Genotype-Phenotype Relationship in XP
	5.7 Cancer Frequency and Age Onset of Skin Cancer in Japanese Patients with XP: Results from the Survey for the XP Patients in 2012 vs 1988
	5.8 Diagnosis, Treatment, and Patient Care
		5.8.1 Sun Protection
		5.8.2 Care for Neurological Symptoms
	References
Chapter 6: Prenatal Diagnosis of Xeroderma Pigmentosum
	6.1 Introduction
	6.2 What Is a Prenatal Diagnosis?
	6.3 XP Genetic Medicine
	6.4 Prenatal Diagnosis of XP-A
	6.5 Current Status of XP Prenatal Diagnosis
	References
Chapter 7: Neurological Disorders and Challenging Intervention in Xeroderma Pigmentosum and Cockayne Syndrome
	7.1 Introduction
	7.2 The Involvement of Oxidative Stress in Neurodegeneration in XP-A and CS
	7.3 Disturbed Metabolism of Monoamine in Xeroderma Pigmentosum Group A and Therapeutic Challenge
	7.4 Disturbed Metabolism of Melatonin in Xeroderma Pigmentosum Group A and Cockayne Syndrome
	7.5 Vascular Changes in Autopsy Brains in Xeroderma Pigmentosum Group A and Cockayne Syndrome
	7.6 Specific Pathology of Oligodendroglia and Microglia in Autopsy Brains in Xeroderma Pigmentosum Group A and Cockayne Syndrome
	7.7 Conclusion
	References
Chapter 8: Xeroderma Pigmentosum in the UK
	8.1 Xeroderma Pigmentosum: Multidisciplinary Model of Care in the UK
		8.1.1 Background
		8.1.2 Applying for Government Funding for a National XP Service
		8.1.3 Design of the Service
			8.1.3.1 Multidisciplinary XP Clinic
			8.1.3.2 Nurse-Led ‘Outreach’ Service
			8.1.3.3 Laboratory Diagnostic Service
			8.1.3.4 Translational Research
	8.2 DNA Repair Testing
	8.3 DNA Repair Gene Mutation Analysis
	8.4 The Multidisciplinary Team (Table 8.2)
		8.4.1 Dermatologist and Dermatological Surgeon
		8.4.2 Ophthalmologist
		8.4.3 Neurodevelopmental Paediatrician and Neurologist
		8.4.4 Clinical Neuropsychologist
		8.4.5 Clinical Geneticist
	8.5 Summary of Findings from 89 XP Patients: 2010–2016
	References
Chapter 9: Cockayne Syndrome: Clinical Aspects
	9.1 Introduction and History
	9.2 Epidemiology
	9.3 Common Symptoms, Clinical Profiles, and Developmental Aspects
	9.4 Neurophysiology
	9.5 Neuroimaging
	9.6 Management and Therapy
		9.6.1 Nutrition
		9.6.2 Renal Failure
		9.6.3 Sleep Disorders and Thermoregulation Problems
		9.6.4 Movement Disorders
		9.6.5 Tooth Decay
		9.6.6 Non-autistic Tendency
		9.6.7 Epilepsy
		9.6.8 Guidelines for CS
	References
Chapter 10: Trichothiodystrophy
	10.1 Introduction
	10.2 Clinical Features
		10.2.1 Photosensitive and Non-photosensitive Forms of TTD
		10.2.2 Incidence and Inheritance
	10.3 Cellular Defects
	10.4 Genes Mutated in TTD: Properties and Functional Activities
		10.4.1 Role of XPB, XPD and p8/TTDA Within the TFIIH Complex
		10.4.2 Role of the Genes Mutated in Non-photosensitive TTD Patients
	10.5 Mutation Pattern and Genotype–Phenotype Relationships
	10.6 Altered Processes/Pathways Underlying TTD Clinical Symptoms
		10.6.1 DNA Repair Defects
		10.6.2 Transcriptional Deregulations
	10.7 Conclusions and Perspectives
	References
Chapter 11: Rothmund–Thomson Syndrome
	11.1 Introduction
	11.2 Epidemiology
	11.3 Cause of Disease
	11.4 Pathological Conditions
	11.5 Diagnosis and Differential Diagnosis
	11.6 Treatment and Prognosis
	References
Chapter 12: Translesion DNA Synthesis
	12.1 Introduction
	12.2 Pol η
		12.2.1 Biological Properties
		12.2.2 Domain Compositions and Mutations in Patients with XP-V
	12.3 Other TLS Polymerases
		12.3.1 Pol ι
		12.3.2 Pol κ
		12.3.3 REV1
		12.3.4 Pol ζ
		12.3.5 Pol θ and Pol ν
		12.3.6 PrimPol
	12.4 Concluding Remarks
	References
Chapter 13: Ataxia-Telangiectasia and Nijmegen Breakage Syndrome
	13.1 Clinical Features of A-T, NBS, and ATLD
	13.2 Interaction Between ATM and NBS1 in DSB Damage Responses
	13.3 Distinct Functions of ATM and NBS1 and Their Relevance to Clinical Phenotypes
	13.4 Novel Role of NBS1 and Its Contribution to NBS-Specific Symptoms
	13.5 Conclusion
	References
Chapter 14: Management of Xeroderma Pigmentosum
	14.1 Introduction
	14.2 UV Management for XP Patients
		14.2.1 UV Management Begins with Identification and Diagnosis of XP Patients
		14.2.2 Layers of UV Protection Prevent Further UV Damage to Patients
		14.2.3 UV Protection for the Face and Eyes Is Critical
	14.3 Management of XP-Related Dermatologic and Ophthalmologic Abnormalities
		14.3.1 Field Treatment for XP Patients
		14.3.2 Surgical Management of Skin Tumors
		14.3.3 Ocular Management
	14.4 Management of the XP Patient at Risk for XP Neurologic Disease
	14.5 Research Studies for Treatment of XP
	14.6 XP Family Social Support
	References