Table Of ContentDiseases of DNA Repair
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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Diseases of DNA Repair
Edited by
Shamim I. Ahmad, BSc, MSc, PhD
School of Science and Technology, Nottingham Trent University
Nottingham, United Kingdom
Springer Science+Business Media, LLC
Landes Bioscience
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Diseases of DNA Repair, edited by Shamim I. Ahmad. Landes Bioscience / Springer Science+Business
Media, LLC dual imprint / Springer series: Advances in Experimental Medicine and Biology.
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Library of Congress Cataloging-in-Publication Data
Diseases of DNA repair / edited by Shamim I. Ahmad.
p. ; cm. -- (Advances in experimental medicine and biology ; v. 685)
Includes bibliographical references and index.
ISBN 978-1-4419-6447-2
1. DNA repair. 2. Genetic disorders. I. Ahmad, Shamim I. II. Series: Advances in experimental medicine
and biology, v. 685. 0065-2598 ;
[DNLM: 1. Genetic Diseases, Inborn--etiology. 2. DNA Repair--physiology. 3. Genetic Diseases,
Inborn--therapy. W1 AD559 v.685 2010 / QZ 50 D611 2010]
QH467.D13 2010
616’.042--dc22
2010011800
DEDICATION TO A SPECIAL PERSON—AMY
It was Wednesday, August 28th
1991, when little angel, Amy, came
into this world in Liverpool Women’s
Hospital, UK. She was born 8-weeks
prematurely weighing merely 2 lbs
11 oz. She was declared to have an
intrauterine growth failure.
Here is what Amy’s mum has to
say about her birth: “Looking back,
we think that it was apparent to
specialists at her birth that there was a
problem—silence when she was born,
her placenta was thin and transparent.
Despite the fact that a geneticist was
brought to see her, nothing was said
to us, and we presumed that this was
a normal birth”.
In the beginning Amy met all her
milestones; she was tiny yet an active
baby. She walked at 13 months, talked
on time and health visitors told Amy’s parents that she would need to wear diving
boots to slow her down. At around 18 months, Amy visited the Genetics Department
of the Alder Hey Children’s Hospital, Liverpool, UK for follow-up, where it was
advised that something was seriously wrong with her—something very rare—and
that, most likely, she wouldn’t grow—they gave it a name—‘Amy syndrome’. One
of several disorders was suspected and tests were done, but no specific diagnosis
was decided upon.
Amy continued to thrive in some ways but not in stature. She was a nightmare
to feed but remained happy and full of energy. She began attending a mainstream
school but couldn’t quite keep up, so was transferred to a Moderate Learning
Difficulties School where she made lots of friends and loved her work. When Amy
was 5 years-old, her parents, while researching on the internet, came across a rare
genetic disorder of DNA repair deficiency called Cockayne syndrome (CS). The
clinical features of this disease and photos of CS children indicated that Amy might
be suffering from this syndrome. Tests were carried out in the UK but no concrete
results came back. Yet her parents strongly believed that Amy had CS.
Around the age of 11, Amy began to deteriorate. Firstly she developed a tremor
and then her balance began to fail. She fell over regularly and began walking with
a very poor posture. She kept asking her mother “What is happening to me?” And
she began to feel very sad. Despite regular visits to a number of doctors, they could
give her very little help. At this stage Amy’s parents took the challenge to ask “What
exactly was wrong with Amy?”.
v
vi Dedication
Amy was 14 when her parents raised enough money to fly to the USA to meet
Dr. Edward Neilan at Boston Children’s Hospital, who was studying CS at that
time. Dr Neilan carried out genetic analyses on Amy’s chromosomes and found a
mutation, which indicated (together with her symptoms and appearance) that she had
atypical CS. When the diagnosis was confirmed, Amy’s mother said “As a mother,
I had known this for nearly 10 years and, in one way, my mind was at peace with
this news but, in another, I was broken-hearted”.
At this time Amy started suffering from tremors. Moreover, she was unable to
eat, drink, dress or carry out her everyday tasks without help.
Subsequently Amy was taken to a neurologist, Dr. Peter Kang, also in Boston,
who prescribed medications for her tremors. Within 10 days Amy’s tremor had
essentially disappeared and this distraught girl was back to her former happy self.
Not only that, but a number of other CS children began taking the same medication
and they too regained some measure of dignity. From then on Amy became desperate
to help other children by participating in several invasive tests, carried out at
experimental levels, and by saying “If it helps others then I want these done”.
Back in England Amy’s parents’ thinking was that they did not want any parent
or child to ever feel as lonely or isolated as they and Amy had. So in 2007 they set
up a charity organization called “Amy and Friends (Cockayne Syndrome Support)”,
and since then have united and helped over 50 families from across the world
suffering from CS. This charity can be found at the website www.amyandfriends.
org (Cockayne syndrome support).
Through this organization Amy and Amy’s parents have brought together a large
number of children suffering from CS, provide them happiness, love and support,
while sharing together heart-breaking moments when children as young as 20 months
and as old as 20 years lose their life. Brave Amy has visited several of her dying
friends and helped them on their way to heaven by saying “Go now, our friends are
waiting to take you, don’t stay here—go and run and play”.
She tells everyone she meets that she is glad to have CS so that she can help
others. She is a pleasure to be around, brings love to those who meet her and once
anyone meets Amy, she is never forgotten. Her teacher once said that what Amy
lacks in stature she makes up in spirit.
Amy is now suffering from an underactive thyroid, kidney failure, hypertension,
diabetes, high cholesterol, raised liver enzymes, a low grade glioma on her thalamus,
kyphosis, lordosis, scoliosis and is stiff and in regular pain. She is unable to do most
things she loves doing and very often feels lonely, despite having so many people
around who love her. She lives now every day wanting to live her life to the fullest
and dreaming of the day when her body is free from this illness.
Never before in my life I met a person who has been suffering so much, yet very
bravely faces the situation and at the same time shows her help, love and affections
to others suffering as her. She must be one of the bravest persons known. She has
touched my heart so much in such a short time that, not only have I decided to work
for this charity organization, but also dedicate this book to her. I gave her an Indian
name—DIYA—which means a ‘clay lamp’ that burns to give light to others.
Shamim I. Ahmad, BSc, MSc, PhD
PREFACE
DNA is an essential component of life and its integrity plays a key role in
sustaining normal life functions including DNA replication, genetic recombination,
transcription and DNA repair. DNA is constantly threatened by numerous
environmental and intrinsic deleterious physical and chemical agents, such as UV
light, ionizing radiation, reactive oxygen species (ROS) and various chemical agents,
which can act as mutagens and carcinogens. Since the integrity of DNA is vital,
nature has endowed living organisms with fairly intricate repair systems involving
a large number of proteins and enzymes participating in a variety of DNA repair
pathways. Interestingly, there exists variation in the ability of individual’s to repair
the damage to DNA.1
Since this book is geared to be used by varied groups of readers such as advanced
students and instructors in the fields of biology and medicine, scientists and more
importantly clinicians, it is considered important to provide brief accounts of the
basics of DNA damage, repair, mutagenesis and cancer.
Studies on DNA damage and repair originated in 1935 in bacteria,2 specifically
in Escherichia coli and subsequently focused on lower eukaryotes such as
Saccharomyces cereviciae and on complex organisms such as humans and plants.
In the last 75 years thousands of scientific papers have been published (23,667
according to PubMed Data, October 2009), and yet we have not reached the goal of
understanding DNA repair systems in humans. Interestingly in the original studies
the damaging agent used was ultraviolet light of type C (180-290 nm).2
Studies on the bacterium E. coli have played important role in our understanding
of DNA damage and repair in humans. A large number of DNA repair systems
have been identified that operate upon different types of damage; these include
photoreactivation repair,3 nucleotide excision repair (NER) of two types, global
genomic repair (GGR) and transcription-coupled repair (TCR),4 mismatch repair
or MMR,5 SOS or error prone repair6 (found in certain prokaryotes involving
more than 40 genes in E. coli and missing in humans), homologous recombination
repair involving RecBCD in E. coli,7 base excision repair or BER (now considered
to be of two types SP-BER or short patch BER and LP-BER or long patch BER,8
non-homologous DNA end joining,9 alkB mechanisms to repair methyl lesions
vii
viii Preface
(and also faulty or damaged RNA)10,11 and translesion synthesis,12 although the latter
might be considered a damage tolerance rather than a repair mechanism. It should be
noted that certain systems such as SOS repair also play roles in modulation of drug
resistance and in secretion and dissemination of virulence in bacteria.13 Likewise
DNA polymerases (5 in E. coli, 8 in S. cereviciae and 15 in humans) that play critical
role in DNA replication, repair, recombination and mutagenesis; certain of these are
specialized polymerases that allow DNA synthesis past lesions in DNA.14
Although a good number of DNA repair enzymes have been conserved through
evolution in species ranging from bacteria to high eukaryotes, DNA repair systems
in humans have evolved more intricately, due to aging, immune systems, cell
compartmentalization including nuclear-lamina,15 presence of mitochondria with their
own DNA, presence of chromatin in DNA,16 respiratory cycle including hypoxia17
etc, involving hundreds of genes, enzymes and proteins.18 As an example, in humans
the two BER sub-pathways are operated by different sets of proteins whereas in
prokaryotes only one set exists.8 In addition, humans have evolved sophisticated
signal transduction networks to sense DNA damage, to trigger a response and to
regulate the consequent gene expression. The first step of the response is cell cycle
arrest followed by the activation of cellular DNA damage responses. The sensor
proteins and signal transduction network are then coordinated to finally repair
the DNA.19 Cells possess the ability to sense whether normal function with DNA
replication, transcription and cell progression can resume. In cases when repair cannot
restore the DNA to its normal form, either due to massive damage or to impairment
of repair system, the cell undergoes senescence or apoptosis.
Eukaryotic chromatin in DNA also plays important roles in maintaining genomic
integrity, and multiple post-translational histone modifications via acetylation,
methylation, phosphorylation and ubiquitination participate in this process.20 The
modifications also play roles in maintaining the chromatin environment, transcription
and replication.
The attempt to repair damage in DNA can have three fates: (i) the DNA is
repaired perfectly, for example as carried out by photoreactivation, also known as
error free repair; (ii) none or incomplete repair, in which case the cell undergoes
senescence or apoptosis (iii) carry out error prone repair and induce mutation, which
is normally long lasting and inheritable, causing inborn errors. Although in many
cases, the occurrence of mutations plays negative role in life (such as, fetal demise or
induction of genetic diseases), in certain cases, it can be advantageous (e.g. survival
of rare antibiotic-resistant mutant bacteria in the presence of antibiotics).
It is estimated that about 6000 single gene mutations cause human diseases
(http://www.ornl.gov/sci/techresources/Human_Genome/medicine/assist.shtml). The
editor of this book estimates that there are about 60-70 diseases associated with defects
in DNA repair systems. This editor has recently published four books addressing
the DNA repair diseases, viz, Fanconi anemia,21 xeroderma pigmentosum,22 ataxia
telangiectasia23 and Cockayne syndrome.24 The purpose of this volume is to present
an updated detailed account of some important additional diseases of DNA repair.
It has not been possible to cover all the DNA repair deficient diseases in this work,
Preface ix
hence diseases such as Bloom’s syndrome, Werner’s syndrome, Nijmegen breakage
syndrome, ataxia telangiectasia-like disorder, RAD 50 deficiency, RIDDLE syndrome
and others will be presented in a forthcoming volume.
In this book, the editor aimed to maintain a balance between the DNA repair
diseases that have been studied exhaustively, well-defined genetic defects in DNA
repair system(s) and those diseases (such as Triple A syndrome) that shows
a tangential association with DNA repair defects and hence more studies are
warranted.
DNA repair diseases can be linked to DNA repair deficiencies in chromosomes
and/or in mitochondria. As the research on human neurodegenerative diseases
progresses, it is becoming apparent that several of them are associated with
mitochondrial dysfunction due mostly to intrinsic oxidative damage. Amyotrophic
lateral sclerosis (ALS) is one such disease (eloquently presented in Chapter 2)
caused by mutations in the gene coding for superoxide dismutase (SOD). Naturally
if SOD (an important scavenger of superoxide radicals) is absent, the endogenous
concentration of intrinsically produced reactive oxygen species (ROS) will increase
and the amount of damage will exceed the ability of the repair complexes that remove
them, and hence the disease. It is, however, still puzzling that mutations in two
other genes, TDP-43 and FUS/TLS, also lead to this disease; this warrants further
studies. In a recent study the editor and his colleagues have identified a number of yet
unidentified enzymes in bacteria that may be responsible for scavenging two types
of ROS, hydroxyl radicals and superoxide radicals (manuscript in preparation).
Alzheimer’s disease is another common neurodegenerative disorder due to
mitochondrial dysfunction, induced mainly by ROS, and this has been fully described
in Chapter 4. In Chapter 5 another neurodegenerative disorder, Huntington’s
disease, is described as caused by unstable expansion of CAG repeats, located in
the 5-prime terminal section of the IT15 gene. In Chapter 6, Katsuno and colleagues
have described another neurodegenerative disorder, spinal and bulbar muscular
atrophy, again caused by expansion of a trinucleotide CAG repeat, which encodes
a polyglutamine tract within the first exon of the androgen receptor gene.
Chapter 7 addresses another neurological disorder, spinocerebellar ataxia with
axonal neoropathy, caused by a specific mutation in the gene coding for tyrosyl
DNA phosphodiesterase. This disorder leads to multiple pathological phenotypes
including neurological disease.
Another neurodegenerative disease, early-onset ataxia with ocular motor
apraxia and hyperalbumenimia/ataxia with oculomotor apraxia, has been
described in Chapter 3, and is caused by a mutation in the APTX gene and consequent
lack of repair of DNA single and double strand breaks leading to neuronal cell
dysfunction and death.
Cornelia de Lange syndrome (CdLS) is another disease with mental
retardation; it has been described in Chapter 11. This is a more complicated disease,
in which severe physiological deformities are observed, mostly facial gestalt. Cells
from patients show a few specific chromosomal rearrangements. It is interesting
to note that dup 3q syndrome has long been considered to be a phenocopy of
