View PDF Version - RePub - Erasmus Universiteit Rotterdam

INTRODUCTION
The genome is under continuous genotoxic stress due, to endogenous and
environmental DNA damaging agents such as solar, and ionizing inadiation,
chemical compounds and oxygen radicals derived from cellular metabolism. DNA
lesions affect the functioning of the genome and are implicated in mutagenesis and
carcinogenesis. Moreover, they have also a sllspected role in aging [1]. To
counteract the obviously deleterious effects of DNA injmy, a network of DNA
repair pathways has evolved. The most versatile mechanism is nucleotide excision
repair (NER) which removes a wide diversity of DNA distorting lesions, among
which the main UV-induced lesions, bulky chemical adducts and some forms of
oxidative damage [2]. The NER process involves the action of at least 30 proteins in
subsequent steps of damage recognition, local opening of the double helix around
the injury and incision of the damaged strand on either side of the lesion. After
excision of the damage-containing oligonucleotide, the resulting gap is filled by
DNA repair synthesis followed by strand ligation [3,4]. Two NER subpathways are
known. Global genome repair (GGR) removes lesions genome wide, while
transcription-coupled repair (TCR) removes transcription-blocking lesions very
efficiently but exclusively from the transcribed strand of active genes. The clinical
consequence of a complete defect in NER is evident from the rare recessive disorder
xeroderma pigmentosum (XP). Seven genes are involved in XP, designated XPA to
XPG. XP patients are very sun-sensitive, display accelerated photoaging of the skin
and have a lOOO-fold increased risk of developing skin tumors. Accelerated
neurodegeneration is noticed in a subset of XP patients [5]. A second human NER
disorder, Cockayne syndrome (CS) is characterized by photosensitivity, which is
remarkably not associated with cancer predisposition [5,6]. Moreover, CS is
considered a segmental progeroid (aging) syndrome because patients have an
overall aged appearance, suffer from postnatal growth failure (cachectic dwarfism),
skeletal abnonnalities (osteoporosis and sclerosis), progressive neurologic
dysfunction (due to dysmyelination), and reduced life expectancy. These symptoms
are absent in XP patients and it is difficult to envision that these are caused by a
defect in NER alone. CS is specifically associated with a defect in the transcriptioncoupled
repair (TCR) sub-pathway [7] due to mutations in the CSA or CSB gene
[8,9]. However, a sole defect in TCR cannot explain the CS features, as some forms
of XP carry a total NER defect and yet fail to express the severe CS symptoms. An
interaction has been found between CSB and RNA polymerase II, suggesting that
impaired transcription in cells of CS patients may be involved in the onset of CS
symptoms. Recently, Leadon et al. provided evidence for a defect in TCR of
oxidative DNA damage in cells of CS patients [10]. This opens up the possibility
that oxidative lesions in actively transcribed DNA contribute to the developmental
defects associated with CS.
106 Chapter 6