Molecular Mechanisms of Xeroderma Pigmentosum

191 Pages·2009·22.64 MB·English

by  James E. Cleaver (auth.)

Molecular Mechanisms of Xeroderma Pigmentosum
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
JOHN D. LAMBRIS, University of Pennsylvania
RODOLFO PAOLETTI, University of Milan
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Molecular Mechanisms
of Xeroderma Pigmentosum
Edited by
Shamim I. Ahmad, MSc, PhD
School of Science and Technology^ Nottingham Trent University, Nottingham,
England
Fumio Hanaoka, PhD
Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
Springer Science+Business Media, LLC
Landes Bioscience
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Molecular Mechanisms of Xeroderma Pigmentosum^ edited by Shamim I. Ahmad and Fumio Hanaoka,
Landes Bioscience / Springer Science+Business Media, LLC dual imprint / Springer series: Advances
in Experimental Medicine and Biology
ISBN: 978-0-387-09598-1
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Library of Congress Cataloging-in-Publication Data
Library of Congress Cataloging-in-Publication Data
Molecular mechanisms of xeroderma pigmentosum / edited by Shamim I. Ahmad, Fumio Hanaoka.
p.; cm. ~ (Advances in experimental medicine and biology ; v. 637)
Includes bibliographical references and index.
ISBN 978-0-387-09598-1
1. Xeroderma pigmentosum-Molecular aspects. 2. DNA repair. I. Ahmad, Shamim I. II. Hanaoka,
Fumio, 1946- III. Series.
[DNLM: 1. Xeroderma Pigmentosum—genetics. 2. DNA Repair Enzymes—genetics. 3. DNA Repair-
Deficiency Disorders-genetics. 4. Xeroderma Pigmentosum-therapy. Wl AD559 v.637 2008 / WR
265 M718 2008]
RL247.M67 2008
616.5'15042-dc22
2008021297
DEDICATION
This book is dedicated to the sufferers of xeroderma pigmentosum and their
parents and relations who painstakingly look after them throughout their suffering,
and to the voluntary organizations and groups working tirelessly for xeroderma
pigmentosum patients.
PREFACE
Xeroderma pigmentosum (XP), meaning parchment skin and pigmentary distur-
bance, is a rare and mostly autosomal recessive genetic disorder that was originally
named by two dermatologists, the Austrian Ferdinand Ritter von Hebra and his Hun-
garian son-in-law Moritz Kaposi in 1874i and 1883.2 The earliest published record
(PubMed) available on the internet is a publication in 1949 by Ulicna-Zapletalova
under the title, "Contribution to the pathogenesis of xeroderma pigmentosum".^ It was
in the late 1960s when James Cleaver (contributor of Chapter 1 of this book), at the
University of California, San Francisco, while working on nucleotide excision repair
(NER), read an article in a local newspaper about XP and soon after obtained a skin
biopsy from a patient suffering from XP that showed that cells from it were deficient
in NER. Thus, his studies led to the discovery that indeed this genetic defect was due
to mutations in DNA repair genes that imbalance the NER pathway.^.s The discovery
paved the way for further exploration of the link between DNA damage, mutagenesis,
neoplastic transformation and DNA repair diseases. Since then, 4,088 papers, includ-
ing excellent reviews, on XP are listed on the internet (PubMed data, February 2008),
and an XP Society has been established in the USA (http://www.xps.org) and an XP
Support Group in the United Kingdom (www.xpsupportgroup.org.uk).
Several clinical features of XP patients, associated with DNA repair deficiency, are
highlighted in Chapter 2, most important being the severe photosensitivity (primarily
to ultraviolet light) of XP patients and subsequent extremely high predisposition to
development of malignant skin neoplasms, including basal cell carcinoma, squamous
cell carcinoma and melanoma, especially on the sim-exposed areas. Additionally, cuta-
neous atrophy and actinic keratosis can occur. Other phenotypes includes neurological
dysfunction (first identified by de Sanctis and Cacchione in 1932)^ and ocular abnormali-
ties. Studies show that 97.3% of XP patients suffer from ocular abnormalities, which
include ocular neoplasm, photophobia, impaired vision, and corneal and conjunctival
abnormalities.7 It is likely that some patients suffer a variety of malignancies; thus, in
a case study in India, it was observed that an XP patient suffered from multiple cuta-
neous malignancies including freckles, letigens, and keratosis, a non-tender ulcerated
nodular lesion on the nose, a nodular ulcerated lesion on the right outer canthus of the
conjunctiva, and a nodular growth on the cheek which turned out to be cancer of the
skin of all types, squamous cell and basal cell carcinoma and malignant melanoma.^
viii Preface
It is likely that patients had been exposed to solar UV for long time to sustain these
phenotypes. Neurological dysfunction is linked to abnormal motor activity, areflexia,
impaired hearing, abnormal EEG and microcephaly.^ Also slow growth, delayed sec-
ondary sexual development and abnormal speech prevail. Some patients are known to
suffer from cancer at the tip of the tongue and the anterior part of the eye.^
In the recent past, much effort has gone into understanding the molecular pathogenesis
of XP in terms of enhanced sensitivity and predisposition of sun-exposed areas of the body
to erythema and various forms of skin cancers. Results of these studies have yielded excit-
ing information on a multitude of protein interactions with various XP proteins involved
in a number of activities associated with repair of UV photoproducts in DNA.
Written by the leading researchers and clinicians in the field, this book provides
a comprehensive treatise on XP. It covers in detail what is known of the 8 XP comple-
mentation groups identified to date. These include XPA, B, C, D, E, F, G and XPV.
In Chapter 1, James E. Cleaver, one of the foimding researchers of XP (and the
winner of Career Award, 2006 from the American Skin Association) has highlighted the
historical aspects of the development of research on XP and the discovery of mutation
in himians affecting DNA repair. On the subject of clinical features of XP, the author
in Chapter 2 has exhaustively covered all aspects of XP epidemiology and phenotypes
including dermatological manifestations, other cancers in XP, and neurological and
ophthahnological manifestations. Also management and prognosis of XP are highlighted.
Although variation exists in sufferers of different complementation groups (Table 2,
Chapter 2) such as skin cancer, opthalmological involvement commonly prevails in all
the sufferers of XP, and the XPA and XPD groups are more prone to neurological dis-
orders. Inherited polymorphisms of DNA repair genes contribute to variations in DNA
repair ability and genetic susceptibility to different cancers. For example, in a recent
study it has been shown that a polymorphism in XPD, codon 751, is associated with the
development of maturity onset cataract and an increased risk of lung cancer.io" Cancer
of various kinds in those parts of the body exposed to UV light (primarily sun) is a
major problem in XP and often leads to premature death; this issue has been described
in Chapter 3. Discovering the link between various XP gene mutations and the phe-
notype may ultimately help define the complex cellular actions of the XP proteins. At
the other end of the spectrum and the book. Chapter 16 details the possible preventive
measures and treatments for XP. However, since the causative agent (solar exposure)
for development of skin cancer in XP patients is well established, one of the most
promising preventive measures is the complete isolation of patients from sunlight and
artificially generated UV lights. Furthermore, in a recent paper, a new method, known
as "gene through the skin", especially suitable for XP patients, has been proposed. 12 The
authors carried out a successful in vitro study, correcting the genetic defect of cells from
XP patients. Therefore the future holds out the possibility of gene therapy or protein
replacement. On the other side of the spectrum is the warning from Reichrath^^ that XP
patients completely protected from sunlight carry a risk of vitamin D deficiency and
related problems. Hence additional care must be taken to monitor patients, providing
supplements to prevent this deficiency and its consequences.
Sunlight emits three forms of ultraviolet light (UVA, UVB and UVC), UVC
being the most potent of the three UV components for damaging DNA. Luckily this
Preface ix
is completely absorbed by the stratospheric ozone layer and cannot reach us. Some
UVB (about 5%) and most UVA (95%), however, penetrate this layer and therefore
XP patients, if exposed to sunlight, receive some UVB and large amounts of UVA.
Experimental data revealed that UVB can generate cyclobutane pyrimidine dimers
(CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4PP), which are highly muta-
genic and carcinogenic. 14 Little evidence is available to show that DNA absorbs UVA
although recently it has been shown that CPD may also be induced by this waveband
of light. Its mechanism of action is considered to be via free radical pathways rather
than direct absorption of UVA by DNA.i^
Over the last 60 years or so most researchers have focussed their studies on UVC,
using a variety of living organisms including animal models, human cell lines and
skin samples, and determining the damage to DNA and to cellular systems, and the
repair mechanisms in the cells to combat the damage. No doubt, knowledge gained
from the UVC studies has been extrapolated on UVB and UVA exposures of himians;
nevertheless, it is also necessary that more attention be given to the importance of
indirect actions of UVA exposure of humans and other living organisms. Furthermore,
it is known that about 20-30% of XP patients also suffer from neurological abnormali-
ties caused by neuronal death in the central and peripheral nervous systems. Since
neural tissues are not exposed to sunlight, the reason for neurodegeneration in XP
patients remains unclear and must be explored. A recent report, however, shows that
8,5'-cyclopurine-2'-deoxynucleosides (cPu), an oxidatively-induced DNA damage,
is repaired by NER and that this lesion is responsible for neurodegeneration in XP
patients lacking NER activity. ^^
Although the deficiency in NER in XP patients has been hypothesised as one reason
why the oxidative DNA lesion, 8-oxoguanine and thymine glycol, cannot be removed
by the same enzyme system responsible for removal of CPD and 6-4PP (see Chapter
12), a key question remains as to how UVA can generate these oxidatively induced
DNA lesions when it cannot reach targets protected from sunlight. Some of the Editor's
(SIA) own research shows that UVA photolysis of certain biological compoimds gener-
ates free radicals and these may be responsible for damage to cellular systems. Free
radicals such as superoxide anions (O2"'), hydroxyl radicals (OH) and singlet oxygen
(1O2) may be produced. ^7,is Also a direct electron transfer (type 1) reaction has been
proposed. 19 It is therefore likely that one or more of these reactions and/or resulting
free radical formation (along with other lesions induced by UVB) may be responsible
for UV-induced skin cancer in XP patients. Hence, more studies must be undertaken
to explore the formation of free radicals by UVA photolysis of biological compounds
and its effect on human health.
Of the eight XP genes so far discovered, seven of them, XP-A through XP-G, play
roles in NER. This ubiquitously found repair process can recognize a variety of DNA
damages including UV-induced CPD and 6-4PP and, using at least 28 NER enzymes
including the seven XP gene products, the repair is carried out. Interestingly three NER
genes are also part of the basal transcription factor TFIIH, and mutations in any one of
11 NER genes have been associated with clinical diseases with at least eight overlap-
ping phenotypes.2o The NER enzyme and the process of NER-induced DNA repair are
covered in Chapter 12.
X Preface
Chapter 4 introduces the XPA gene (located at 9q22), one of the key NER genes.
Its biological role is to recognize and promote the binding of repair complex to DNA at
the damaged site, including CPD and 6-4PP induced by UV light. The 31 kDa protein
forms a core of the incision complex by interacting with a number of other XP proteins
(see Fig. 2, Chapter 4). The complex is then responsible for recognizing kinks in DNA
caused by a variety of other damaging agents (see refs. 16, 21, 75, 90 of Chapter 4) and
makes an incision leading to removal of the damaged section and its replacement by
polymerization of DNA with subsequent ligation of the newly synthesized strand. In a
recent study, however, it has been shown that purified XPA and the minimal DNA-binding
domain of XPA can, fully and preferentially, bind to mitomycin C-DNA crosslinks in
the absence of other proteins fi-om NER.21 Another recent study shows that cells that
overexpress the HMGAl (high mobility group Al) proteins show deficiency in NER
because these non-histone proteins are involved in inhibiting XPA expression, resulting
in increased UV sensitivity.22
Chapter 5 describes AP5 and JLPD genes (located at 2ql4 and 19ql3, respectively),
their products and biological roles; XPB is a helicase and together with XPD products
constitute components of TFIIH. This complex is composed of 10 proteins, five of
which (p8, p34, p44, p52, p62) make a tight complex along with XPB, and XPD is less
tightly associated with the CAK subcomplex containing cyclin H, cdk? and MAT 1.23 The
DNA-dependent helicase activity of XPB and XPD is important in transcriptional initia-
tion and the NER process although the molecular mechanism of these two gene products
in NER is poorly understood. In a recent study it has been shown that the p52 subunit
of TFIIH interacts with XPB and stimulates its ATPase activity.24 XPB is a rare disease
compared to other XP forms. Also mutation in XPD can lead to bladder cancer.25
XPC (gene location at 3p25) is the most commonly prevailing mutational site of
all XP genetic defects. It is a key protein involved in DNA repair, damaged by a variety
of agents including UV light. The primary role of this protein is to recognize the dam-
age and allow NER to complete the repair process. In addition to participating in NER
repair, XPC has also been shown to participate in BER (base excision repair), especially
of those lesions induced oxidatively such as 7,8-dihydroxy-8-oxoguanine and other
single base modifications that are repaired by BER.26 In order to recognize damage, the
protein forms a complex with Rad23p orthologs and centrin-2. Thus DNA damage in
XPC patients is not recognized and remains unrepaired, and XPC phenotype prevails.
In a recent study it has been shown that INGlb (a ubiquitous protein involved in a large
number of biological activities including senescence, cell cycle arrest, apoptosis and
DNA repair) enhances NER repair only in XPC proficient cells and via XPA, implying
an essential role of INGlb in early and better access of NER machinery via associa-
tion with chromatin to the sites of the lesion.27 A recent study fi-om China found a link
between XPC deficiency and promotion and progression of bladder cancer, and also
cellular development of resistance against anticancer drugs.28 Further roles of XPC and
its biological activities have been described in Chapter 6.
Patients suffering fi*om a defect in XPE, on the other hand, are rare and the subgroup
is considered to be one of the mildest of XP forms. XPE gene is located on chromosome
11, at Ilql2-ql3 for DDBl and llpll-pl2 for DDB2; thus there are two components
of the XPE protein, damaged DNA binding proteins 1 and 2. All XPE patients so far
identified carry mutation in the DDB2 gene. It is suggested that this protein is involved