DNA Repair Disorders

222 Pages·2019·5.556 MB·English

by  Chikako Nishigori, Kaoru Sugasawa

DNA Repair
Disorders
Chikako Nishigori
Kaoru Sugasawa
Editors
123
DNA Repair Disorders
Chikako Nishigori • Kaoru Sugasawa
Editors
DNA Repair Disorders
Editors
Chikako Nishigori Kaoru Sugasawa
Department of Dermatology Biosignal Research Center
Graduate School of Medicine, Kobe University Kobe University
Kobe Kobe
Japan Japan
ISBN 978-981-10-6721-1 ISBN 978-981-10-6722-8 (eBook)
https://doi.org/10.1007/978-981-10-6722-8
Library of Congress Control Number: 2018959112
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Preface
Xeroderma pigmentosum (XP) is an autosomal recessive hereditary photosensitive
disease, in which patients display extreme hypersensitivity to ultraviolet radiation
(UVR) because of the deficiency in the ability to repair the UVR-induced DNA
lesions. Although the existence of the disease had been known since the first case
report on XP by a dermatologist, Kaposi, in 1883, the cause of XP was at length
discovered in 1968, 85 years after the first case report. This year marks the 50th
anniversary of the discovery of the cause of XP, a deficiency in nucleotide excision
repair (NER), by James E.  Cleaver. NER is an indispensable DNA repair
mechanism for all living things on earth to remove various forms of DNA lesions
from their genomic DNA, including UVR-induced DNA lesions, such as
cyclobutane pyrimidine dimers and (6-4)photoproducts. In this sense, NER
involves in an essential mechanism for living things and recently it has been shown
that NER is closely involved in the biologically fundamental role such as
transcription and replication. Therefore the deficiency in NER results in a
disastrous condition. In this book we focused on the clinical aspects of DNA repair
disorders. We would like to delineate the outcome of the deficiency of DNA repair
so that we will come to know the essence of the DNA repair mechanisms. The
authors are experts in this subject, and the publication of this book is timely
because a Nobel Prize was given to the scientists who discovered the mechanisms
of the NER, and the readers may be interested in what will become of individuals
who are deficient in DNA repair.
Kobe, Japan Chikako Nishigori
Kobe, Japan Kaoru Sugasawa
v
Contents
1 Molecular Mechanism of DNA Damage Recognition
for Global Genomic Nucleotide Excision Repair:
A Defense System Against UV-Induced Skin Cancer . . . . . . . . . . . . . 1
Kaoru Sugasawa
2 Disorders with Deficiency in TC-NER: Molecular
Pathogenesis of Cockayne Syndrome and UV-Sensitive
Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Chaowan Guo and Tomoo Ogi
3 Neurological Symptoms in Xeroderma Pigmentosum . . . . . . . . . . . . . 41
Fumio Kanda, Takehiro Ueda, and Chikako Nishigori
4 Hearing Impairment in Xeroderma Pigmentosum: Animal
Models and Human Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Takeshi Fujita and Daisuke Yamashita
5 Epidemiological Study of Xeroderma Pigmentosum
in Japan: Genotype-Phenotype Relationship . . . . . . . . . . . . . . . . . . . . 59
Chikako Nishigori and Eiji Nakano
6 Prenatal Diagnosis of Xeroderma Pigmentosum . . . . . . . . . . . . . . . . . 77
Shinichi Moriwaki
7 Neurological Disorders and Challenging Intervention
in Xeroderma Pigmentosum and Cockayne Syndrome . . . . . . . . . . . . 87
Masaharu Hayashi
8 Xeroderma Pigmentosum in the UK . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Hiva Fassihi, Isabel Garrood, Natalie Chandler, Shehla Mohammed,
Alan R. Lehmann, and Robert Sarkany
vii
viii Contents
9 Cockayne Syndrome: Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . 115
Masaya Kubota
10 Trichothiodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Donata Orioli and Miria Stefanini
11 Rothmund–Thomson Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Hideo Kaneko
12 Translesion DNA Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Chikahide Masutani and Fumio Hanaoka
13 Ataxia-Telangiectasia and Nijmegen Breakage Syndrome . . . . . . . . . 191
Junya Kobayashi
14 Management of Xeroderma Pigmentosum . . . . . . . . . . . . . . . . . . . . . . 203
Deborah Tamura, Ryusuke Ono, John J. DiGiovanna,
and Kenneth H. Kraemer
Chapter 1
Molecular Mechanism of DNA Damage
Recognition for Global Genomic
Nucleotide Excision Repair: A Defense
System Against UV-Induced Skin Cancer
Kaoru Sugasawa
Abstract Nucleotide excision repair (NER) is a versatile DNA repair pathway
responsible for removal of ultraviolet light (UV)-induced DNA photolesions from
the genome. In mammals, NER operating throughout the genome decreases the risk
of UV-induced mutagenesis arising due to DNA translesion synthesis across pho-
tolesions on template DNA strands and thereby contributes to suppression of skin
cancer. Lesion recognition for global genomic NER relies on multiple xeroderma
pigmentosum (XP)-related protein factors, XPC, UV-DDB, TFIIH, and XPA, each
of which probes for a different aspect of abnormal DNA structure. A combination
of diverse strategies is likely required to achieve the broad substrate specificity,
efficiency, and accuracy of this DNA repair system. To regulate this elaborate sys-
tem in vivo, post-translational protein modifications, such as ubiquitination, and
higher-order chromatin structures also play important roles.
Keywords Nucleotide excision repair · Xeroderma pigmentosum · DNA damage
recognition · XPC · UV-DDB · Transcription factor IIH (TFIIH) · XPA · Ubiquitination
Chromatin · Histone
1.1 Introduction
Among the complex clinical symptoms associated with xeroderma pigmentosum
(XP), the predisposition to skin cancer is an important diagnostic hallmark [1].
Mutagenesis following ultraviolet light (UV)-induced DNA damage is a fundamen-
tal cause of skin cancer. In patients with XP, the risk of mutagenesis is elevated
tremendously by a hereditary defect in one of two biological processes, nucleotide
excision repair (NER) or DNA translesion synthesis (TLS) [2].
K. Sugasawa
Biosignal Research Center, Kobe University, Kobe, Hyogo, Japan
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2019 1
C. Nishigori, K. Sugasawa (eds.), DNA Repair Disorders,
https://doi.org/10.1007/978-981-10-6722-8_1
2 K. Sugasawa
NER is an important DNA repair pathway that can remove various types of struc-
turally unrelated DNA lesions from genomic DNA [3]. In many species, including
humans, NER is exclusively responsible for repair of major UV-induced DNA
lesions (i.e., dipyrimidinic photolesions). Consequently, a defect in NER can result
in accumulation of unrepaired photolesions in genomic DNA of skin cells. Such
lesions interfere with normal processes of DNA replication, transcription, and other
aspects of DNA metabolism. Mutations can then arise when TLS incorporates
incorrect nucleotides opposite photolesions on the template DNA strand [4, 5].
According to this widely accepted model for skin carcinogenesis, global coverage
of the genome by NER functions as a defense system against UV-induced skin can-
cer by decreasing the frequency of collisions between DNA replication forks and
photolesions. Sustained DNA lesions block transcriptional elongation but can be
removed from transcribed DNA strands by a specialized NER sub-pathway called
transcription-coupled NER, which is reviewed in another chapter of this book.
By the end of the twentieth century, the causative genes for all known genetic
complementation groups of XP had been identified; among them, seven groups
(XP-A through XP-G) are associated with defective NER. Extensive studies of
these gene products have contributed to our understanding of the basic molecular
mechanisms of NER [6]. It has been also revealed that NER is subject to elaborate
regulation, which involves post-translational protein modifications and alteration of
chromatin structures. This chapter reviews our current knowledge on the mecha-
nism and regulation of mammalian global genomic NER (GG-NER), especially the
DNA damage recognition step.
1.2 Mammalian NER Pathways
Among the various DNA repair pathways, a remarkable characteristic of NER is its
extremely broad substrate specificity. Typical examples include the following: (1)
UV-induced photolesions, such as cyclobutane pyrimidine dimers (CPDs) and
pyrimidine (6-4) pyrimidone photoproducts (6-4PPs); (2) intrastrand crosslinks
caused by bifunctional chemical compounds (e.g., cisplatin); and (3) bulky base
adducts induced by various chemical carcinogens, including benzo[a]pyrene and
acetylaminofluorene (AAF) [3]. Although most of these lesions are induced by
environmental factors, NER can also handle certain types of endogenous oxidative
DNA damage, such as 5′,8-cyclo-2′-deoxypurine lesions [7, 8], albeit with rela-
tively low efficiency. In addition, NER is thought to participate in repair of highly
detrimental interstrand crosslink lesions [9] that can be induced not only by cancer
chemotherapeutic agents such as cisplatin and mitomycin C but also by aldehydes
from endogenous and exogenous sources [10, 11].
Mammalian NER is an elaborate system involving more than 30 polypeptides,
which can be dissected into several reaction steps (Fig. 1.1).
1 Molecular Mechanism of DNA Damage Recognition 3
DNA damage rejoining of DNA strands
(UV, chemicals) intact DNA DNA ligase
CUL4-RBX1 (Lig I or XRCC1/Lig IIIα)
DDB1 CPD
6-4PP
DDB2
lesion
recognition 6-4PP
bulky adduct
XPC-RAD23-CETN2
TFIIH DNA repair synthesis
XPA (XPB, XPD, TTDA) DNA polymerase 3’ incision
(Pol δ/ε/κ)
PCNA
RFC
lesion verification XPG ERCC1-XPF
RPA
unwinding of DNA duplex 5’ incision
Fig. 1.1 Model of the molecular mechanism of mammalian global genomic NER. See text for
details
1.2.1 Lesion Recognition
To initiate a repair reaction, it is crucial to sense the existence of a relevant lesion
and determine its precise location within the DNA. In mammalian GG-NER, the
protein complex containing the XPC gene product plays a central role in this key
step [12–14]. The XPC protein complex has the potential to interact with various
types of abnormal DNA (see below), thus serving as a highly versatile lesion recog-
nition factor. On the other hand, a more specialized damage recognition pathway
has evolved to ensure efficient repair of UV-induced photolesions. The UV-damaged
DNA-binding protein complex (UV-DDB) exhibits exceptionally high binding
affinity and specificity for photolesions (both CPDs and 6-4PPs) and promotes
recruitment of XPC to the damaged DNA sites [15–17].
At transcriptionally active gene loci, lesions generated on transcribed DNA
strands can be sensed by elongating RNA polymerases as a result of blockage of
their translocation, efficiently triggering a specific sub-pathway of NER called
transcription- coupled NER (TC-NER) [18]. Because RNA polymerase functions as
the primary lesion sensor, both XPC and UV-DDB are dispensable for TC-NER. By
contrast, some gene products implicated in Cockayne syndrome and UV-sensitive
syndrome (CSA, CSB, and UVSSA) are required specifically for TC-NER, but not
for GG-NER.