HUMAN PHOTOSENSITIVE DISEASES OF DNA REPAIR
James E. Cleaver
Auerback Melanoma Laboratory
Box 0808, UCSF Cancer Center
University of California
San Francisco, CA 94143-0808
jcleaver@cc.ucsf.edu
DNA Damage From Ultraviolet Light
Ultraviolet (UV) radiation covers three wavelength ranges: UVA
(320-400 nm), UVB (290-320 nm), and UVC (240-290 nm). UVA is photocarcinogenic and involved in photoaging, but is weakly absorbed in DNA and protein, and involves other chromophores that lead to reactive oxygen species (ROS), which secondarily cause damage to DNA (Tyrrell and Keyse, 1990). UVB overlaps the upper end of the DNA and protein absorption spectra, is present in sunlight, and is the range mainly responsible for skin cancer through direct photochemical damage to DNA. UVC is not present in sunlight, but is readily produced by low-pressure mercury sterilizing lamps (254 nm) that coincides with the peak of DNA absorption (260 nm), and is used extensively in experimental studies. Absorption of UV by stratospheric ozone results in negligible radiation shorter than 300 nm reaching the earth's surface.
The proliferating cells in the basal layer of the skin epithelium are protected by melanin pigment and keratin layers; intracellular defenses depend upon the repair of DNA damage, antioxidant enzymes (superoxide dismutase, glutathione reductase, etc.), endogenous free radical quenchers, and inducible detoxifying enzymes and biochemical systems (Tyrrell and Keyse, 1990). Although the important wavelength range responsible for skin cancer is UVB, UVA cannot be excluded because of evidence that it may indirectly form thymine dimers in skin (Courdavault et al., 2004; Mouret et al., 2006) and is carcinogenic in mice (Sterenborg and van der Leun, 1990).
Sunlight Induced Photoproducts In DNA
The absorption spectrum of DNA correlates well with UV-induced lethality, mutation, and photoproduct formation (Jones et al., 1987; Niggli and Cerutti, 1983; Pfeiffer et al., 1991, 1992; Tyrrell and Pidoux, 1987). Dimerizations between adjacent pyrimidines are the most prevalent photoproducts found in DNA. The most important are the cyclobutane pyrimidine dimer (CPD) and, at about 25% of the frequency, the [6-4] pyrimidine dimer [(6-4)PD], which are preferentially induced at thymine-cytosine dipyrimidines (Mitchell and Cleaver, 1990). The relative proportion of DNA photoproducts varies across the UV spectrum. The distribution of these photoproducts in human chromatin, and their repair, depends on base sequence, secondary DNA structure, and DNA-protein interactions (Lange et al., 2008; Mitchell et al., 1991, 1992; Pfeiffer et al., 1992). Cytosine absorbs longer wavelengths of UV more efficiently than thymine, and therefore CPDs containing cytosine are formed more readily after UVB irradiation (Ellison and Childs, 1981) and may play a major role in UVB (solar) mutagenesis. The [6-4]PD can undergo a UVB-dependent conversion to its valence photoisomer, the Dewar pyrimidinone (Taylor and Cohrs, 1987). Other less common lesions include purine-purine and purine-pyrimidine photoadducts, photohydrations, and photooxidations (Cadet and Vigney, 1990).
UVA primarily produces damage indirectly through ROS, which can be reduced by free radical scavengers (Tyrrell and Pidoux, 1986). ROS can react with DNA to form base damage, strand breaks and DNA-protein crosslinks (see Module) that may be an important pathogenic component of sunlight (Jones et al., 1987; Tyrrell and Pidoux, 1987). Recent evidence suggests that UVA may also induce significant levels of CPDs in human cells by photosensitized triplet energy transfer, and that these lesions should be taken into account to fully understand the biological effects of UVA (Courdavault et al., 2004).
Photosensitive And DNA Repair Deficient Diseases
Xeroderma pigmentosum (XP) was the first nucleotide excision repair (NER) disease to be identified (Cleaver, 1968). This discovery linked a human mutation to solar-sensitivity and cancer, and provided an impetus to the concept of somatic mutations and genomic instability as a causative factor in human cancer. The complete family of NER-related diseases now include (Figure 1, Table 1): XP itself, XP with neurological complications, the XP variant, Cockayne syndrome (CS), the cerebro-oculo-facio-skeletal syndrome (COFS), a mild UV-sensitive syndrome (UVs), trichothiodystrophy (TTD), and patients with combined symptoms of XP/CS and XP/TTD (Bootsma et al., 1998; Cleaver and Crowley, 2002; Kraemer et al., 1987; Thompson, 1998). These diseases show overlapping symptoms associated with cancer, developmental delay, immunological defects, neurodegeneration, retinal degeneration, and premature aging. The range of symptoms appears to be due in part to the impairment of the growth hormone-insulin-like growth factor 1 (IGF-1) axis associated with organ damage (van der Pluijm et al., 2006).
Figure 1. (A, B) Two XP patients provisionally designated as XP-D and XP-C respectively; the patient in panel A subsequently showed decline of the central nervous system. (C, D) A CS patient at ages 4 and almost 7 yr, respectively. (E, F) two TTD patients. Reproduced from Thompson, in DNA Repair in Higher Eukaryotes, Chapter 18, 1988, with permission of Springer Science and Business Media.
Reproduced from Thompson, in DNA Repair in Higher Eukaryotes, Chapter 18, 1988, with permission of Springer Science and Business Media.
a. Traits that are hallmarks of the disease are indicated by (++), and traits that are sometimes associated with the disorder are indicated by (+); unassociated traits are shown by (-).
b. These features are present in about 20% of XP patients. The molecular basis of the neurological dysfunctions in XP differs from that of CS and TTD. Demyelination of neurons is seen in TTD and CS. XP involves primary neuronal degeneration thought to be related to the severity of repair deficiency and metabolic damage to DNA.
c. The facial abnormalities of TTD and CS overlap in term of protruding ears. TTD often has receding chin and small thin or beaked nose, whereas CS tends to have large nose and projecting jaw.
d. XP-C is exceptional in being deficient in repairing bulk DNA, but proficient in transcription coupled repair (TCR).
Xeroderma Pigmentosum (XP)
XP is a rare human, autosomally inherited, skin and neurodegenerative disease in which exposure to normal sunlight can result in a very high incidence of skin and mucous membrane cancer (Cleaver, 1968). The disease occurs at a frequency of 2.3 per million in Western Europe, including both indigenous and immigrant populations; when these are segregated the rate is 0.9 per million for indigenous population (Kleijer et al., 2008). Heterozygotes are unaffected, in contrast to the severity of symptoms in the homozygotes (Kraemer et al., 1987, 1994). UVB is the shorter wavelength radiation in sunlight responsible for most sun-induced cancers in the general population as well as in XP patients. These cancers include squamous and basal cell carcinomas and melanomas caused by exposure to solar ultraviolet radiation. The symptoms of XP begin in early life with the first exposures to sunlight, the median age of onset being 1-2 years of age, with skin rapidly exhibiting the signs associated with years of sun exposure. Some patients present with severe sunburn and blistering, whereas others present with early extensive freckling. Pigmentation is patchy, and skin shows atrophy and telangiectasia with the development of basal and squamous cell carcinomas and melanomas.
The relative incidence of the various forms of skin cancers in XP patients, including nonmelanoma skin cancers and melanomas, is similar to that in the general population (Kraemer et al., 1994). Cancer incidence for those individuals under 20 years of age is 2,000 times that seen in the general population. Progressive neurologic degeneration occurs in a significant number of patients, which can be correlated with mutations in specific XP genes (XPA, B, D, G). There may be a reduction in life span associated with the progression of cancer or neurologic degeneration, but a specific effect on lifespan itself has not been observed even in cultured cells (Cleaver, 1984).
There has been some question of whether XP patients show a higher than normal incidence of internal cancers (Kraemer et al., 1984), but answers are bedeviled by small sample sizes and the possibility that the low normal levels of vitamin D associated with sun protection of XP patients (Sollitto et al., 1997), could influence the internal cancer rates (Dixon et al., 2005; Garland and Garland, 1980; Spina et al., 2006).
Cockayne Syndrome (CS)
CS is an autosomal recessive disease characterized by cachectic dwarfism, retinopathy, microcephaly, deafness, neural defects, and retardation of growth and development after birth (Figure 1) (Nance and Berry, 1992). The cerebellum shows a distinctive loss of Pyrkinje cells associated with regulating balance and walking. They have a typical facial appearance with sunken eyes and a beaked nose, and projecting jaw. CS patients are sun sensitive, but do not develop cancers, setting this disease apart from XP, and carry mutations in one of two genes, CSA and CSB, with group A being the more common (Lehmann, 1982). In addition there are patients who show combined XP and XP/CS symptoms, some of whom have mutations in XPB, XPD or XPG (Weeda et al., 1990). The CS gene products are involved in coupling excision repair to transcription (Hoeijmakers, 2001). They may be involved in the ubiquitination and degradation of stalled RNA pol II at damaged sites (Bregman et al., 1996; Groisman et al., 2003). Cockayne syndrome may be considered to encompass a wide range of diseases from the mild UVs syndrome, which only shows photosensitivity, through the major groups known clinically as CS I and II, though to the most severe neonatal lethal disorder, COFS (see below).
Trichothiodystrophy (TTD)
TTD is a rare autosomal recessive disorder characterized by sulfur-deficient brittle hair and ichthyosis (Figure 1) (Itin et al., 2001). Hair shafts split longitudinally into small fibers, and this brittleness is associated with levels of cysteine/cystine in hair proteins that are 15 to 50% of those in normal individuals. The hair has characteristic "tiger-tail" banding visible under polarized light. The patients often have an unusual facial appearance, with protruding ears and a receding chin. Mental abilities range from low normal to severe retardation (Lehmann et al., 1988).
A recent systematic literature review (Kraemer et al., 2008) identified 112 patients ranging from 12 weeks of age to 47 years (median 6 years). In addition to hair abnormalities, common features reported were developmental delay and intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal physical characteristics at birth (55%), ocular abnormalities (51%), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%), and defective DNA repair (37%). There was high mortality, with 19 deaths under age 10 years (13 infection-related), which is 20-fold higher compared to the US population. The spectrum of clinical features varied from mild disease with only hair involvement, to severe disease with profound developmental defects, recurrent infections, and a high mortality at a young age. Abnormal characteristics at birth and pregnancy complications, unrecognized but common features of TTD, suggest a role for DNA repair genes in normal fetal development.
Several categories of the disease can be recognized on the basis of cellular responses to UV damage and the affected genes. Severe photosensitive and NER defective cases of TTD involve components of the transcription factor TFIIH (Broughton et al., 1990; Itin et al., 2001): XPB, XPD or a small stabilizing factor p8 (Giglia-Mari et al., 2004; Ranish et al., 2004). There are also nonphotosensitive TTD cases that involve at least one more gene TTDN1 (Botta et al., 2007). Although TTD patients do not exhibit increased incidence of skin cancer, corresponding mice with a human TTD mutation are sensitive to increased UV-induced skin cancer, indicating important differences between the human and mouse models (de Boer et al., 1998a; de Boer et al., 1998b).
XP-CS and XP-TTD Syndrome
There are several examples of patients who exhibit combined symptoms of XP and other developmental and neurological disorders of CS or TTD. These have generally been found to correspond to mutations in the XPB, XPD or XPG genes.
Cerebro-Oculo-Facio Skeletal (COFS) Syndrome
COFS syndrome is an autosomal, recessively inherited and rapidly progressive, neurologic disorder. The disease leads to brain microcephaly and atrophy with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. COFS appears to be a particularly severe developmental and neurological expression of mutations in CSB, XPG , XPD and ERCC1 (Graham et al., 2001; Jaspers et al., 2007; Laugel et al., 2008b; Niedernhofer et al., 2006).
The XP, CS and TTD Genes
Eight genes have been identified among XP patients (Thompson, 1998): seven are involved in nucleotide excision repair (XPA-XPG), and one, the XP variant, is involved in the replication of damaged DNA on the leading strand (Svoboda et al., 1998). Mutations in any of the genes XPA to XPG result in reductions in the ability of cells to excise cyclobutane pyrimidine dimers, [6-4] photoproducts, and other bulky carcinogen adducts from DNA. The functions of most of the gene products in the NER process have been identified, and mutations located in each of the genes have begun to be correlated with cellular functions, and with the severity of disease (Cleaver, 2004, 2005; Cleaver and Crowley, 2002; Hoeijmakers, 2001). Several of the gene products occur in heterodimeric complexes with proteins that are essential for their stability and function: the XPC protein is complexed with HHR23B; the 48 kDa XPE protein (DDB2) is complexed with a larger 127 kDa subunit (DDB1); and the XPF protein is complexed with the ERCC1 protein (ERCC = excision repair cross complementing, to indicate a human gene correcting a rodent cell mutation). Curiously, in each of these examples, mutations associated with XP have mainly been found in one of the members of the heterodimer. In addition, the XPB and XPD helicases exist as components of TFIIH, which is a basal transcription initiation factor containing at least ten proteins (Hoeijmakers et al., 1996).
XPA
XPA is located on chromosome 9q34.1 and encodes a 273 amino acid Zn2+ finger protein (XPA) that participates in photoproduct recognition and DNA binding (Asahina et al., 1994; Jones and Wood, 1993; Miura et al., 1991). The earliest damage recognition step that has been reported involves XPC (Sugasawa et al., 1998). This binding may be followed by the formation of a quasi-stable complex consisting of XPA, XPC, human single-strand binding protein (RPA/HSSB), and TFIIH, which then acts as a nucleation site for binding of the incision/excision enzymes (Mu et al., 1997). Of the two major photoproducts, [6-4] photoproducts and cyclobutane pyrimidine dimers, XPA alone shows only weak binding to pyrimidine dimers (He et al., 1995; Jones and Wood, 1993; Li et al., 1995b, 1995c; Miura et al., 1991; Robins et al., 1991). The XPA-RPA complex appears to bind to damaged sites in DNA once they have been recognized and bound by either XPC/HHR23B in nontranscribed regions of DNA (Sugasawa et al., 1998), or by stalled RNA polymerase II transcription machinery in transcribed regions (Hanawalt, 1994). XPA is also required for the repair of oxidative damage in mitochondrial DNA (Driggers et al., 1996), indicating potential overlap between nucleotide and base excision repair, also found with XPG (Cooper et al., 1997).
Figure 2. Location of the mutations in the XPA gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from States et al., Human Mutation 12:103-113, 1998, with permission of John Wiley and Sons Inc.
The gene is encoded in 6 exons distributed over 22-25 kb of genomic DNA (Satokata et al., 1993; Topping et al., 1995), and mutations have been found throughout the gene with the exception of exon I. The first exon is essential for nuclear localization, but not for DNA repair when the protein is expressed at high levels (Miyamoto et al., 1992). Exon II encodes a domain for binding to ERCC1, a component of the heterodimeric 5' endonuclease composed of ERCC1 and XPF (ERCC4) (Li et al., 1995, 1995b), and deletion of the ERCC1 binding region in vitro generates a dominant negative phenotype (Li et al., 1995b). Exon III encodes the Zn2+ finger that binds RPA (Li et al., 1995a). Exons IV and V comprise the DNA binding domain (Ikegami et al., 1998; Kuraoka et al., 1996). Exon VI interacts with the TFIIH complex (Park et al., 1995).
Two classes of XP-A patients are known, those with severe central nervous system disorders involving sensoneural deafness, reduced nerve conduction, difficulty walking, and occasionally microcephaly, and those with only skin sensitivity and cancer. The more severe cases tend to have both alleles with mutations that occur within the DNA binding region of the protein, often resulting in truncation, and detailed analysis and diagrammatic representation has been published (States et al., 1998). Severe cases in both Japan and Africa have been reported with mutations at the same site, the last nucleotide of intron 3. Milder cases generally have at least one allele with a mutation outside of the DNA binding region, such as the exon 6 (R228ter) mutation common in Tunisian patients (Nishigori et al., 1993, 1994), and other cases (Cleaver et al., 1995). A few other mild cases have mutations close to a splice site such that alternative splicing may allow the persistence of a low level of normal protein.
XPB (ERCC3)
XPB is located on chromosome 2q21, and encodes a 782 amino acid 3'-5' helicase, the p89 subunit of TFIIH (Coin et al., 1999). The gene is also known as ERCC3. The helicase may be involved in unwinding the DNA 5'-ward of a damaged base. The ATPase activity is required to "lock" the pre-incision complex in place prior to cleavage of the DNA strands (Coin et al., 2007; Oh et al., 2007; Reardon and Sancar, 2005; Wakasugi and Sancar, 1999). The N terminus of the protein interacts with the XPD and XPG proteins, whereas the C terminus is required for the 5' cleavage during excision repair (Evans et al., 1997). The protein also interacts with the BCR-ABL oncoprotein, although its potential role in hematopoeitic malignancies is unknown (Takeda et al., 1999). Only a small number of patients are known in this complementation group, and their clinical symptoms are extremely varied with mutations at both extremes of the gene.
Figure 3. Location of the mutations in the XPB gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Itin et al., J. Amer. Acad. Dermatology 44:891-920, 2001, with permission of Elsevier.
XPC
XPC is located on chromosome 3p25.1, and encodes a 940 amino acid single-stranded DNA binding protein that is essential for the repair of nontranscribed regions of the genome. XP-C patients are among the more common form of XP, and exhibit predominantly skin cancer without neurological disorders. The protein acts in the initial step of damage recognition in these regions (Sugasawa et al., 1998), but is then released from the pre-incision complex before strand incision occurs (Wakasugi and Sancar, 1998), a process that involves ubiquitination by the DDB1/2 (XPE) ubiquitin ligase (Sugasawa et al., 2005). XPC exists in vivo in a tight complex with another protein HHR23B, which is encoded by a closely linked (within 650 kb) gene to XPC (Masutani et al., 1994). Mutations in HHR23B are not known to be associated with any human disorder, although the mutations in the corresponding gene in yeast makes cells UV sensitive.
Figure 4. Location of mutations in the XPC gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Chavanne et al., Cancer Research 60: 1974-1982, 2000, with permission of the American Association of Cancer Research Inc.
XPD (ERCC2)
The XPD gene is located on chromosome 19q13.2, and encodes a 760 amino acid 5'-3' helicase, a component of transcription factor TFIIH (Bootsma et al., 1998; Coin et al., 1998, 1999). The gene, encoded in 23 exons, is also known as ERCC2. The helicase may be involved in 3'-ward unwinding of the DNA in the vicinity of a damaged base, and in the opposite direction to the XPB helicase. The phenotypes of mutations in this gene are among the most complex of all XP groups, being associated with three different clinical disorders: XP group D, TTD, or a rare combination of XP and CS. Most TTD patients exhibiting UV sensitivity fall into the XP-D complementation group (Botta et al., 1998; Stefanini et al., 1993).
Figure 5. Location of the mutations in the XPD gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. The mutations associated with the three diseases XP, CS and TTD are identified by different colors. Reproduced from Itin et al., J. Amer. Acad. Dermatology 44:891-920, 2001, with permission of Elsevier.
Since the clinical characteristics of XP and TTD are so different, mutation analysis has sought to explain how two dissimilar disorders are associated with the same gene. The result of such studies is that all mutations thus far reported appear to be specific for the disease, and only missense mutations are important for disease, because the loss of function mutations are lethal, although the severity can be influenced by gene dosage (Botta et al., 1998). As a member of the TFIIH complex, XPD is an essential protein for transcription and cell viability (de Boer et al., 1998b). Thus, no patient can have two null alleles. The interpretation of XPD mutations is confounded by the fact that in several cases, XP-D and TTD patients have an allele in common, suggesting that the second alleles determine the clinical presentation. By examining the phenotype in Schizosaccharomyces pombe of mutations homologous to those present in these shared alleles, the S. pombe mutations were shown to behave as null mutations (Taylor et al., 1997). Therefore, by extrapolation these common alleles can conveniently be regarded as nonfunctional, and playing no direct role in the specific disease.
Examination of the distribution of mutations within the XPD protein reveals that essentially all XP-D mutations fall within one of the conserved helicase domains (Koonin, 1993). This pattern indicates that these mutations can be expected to reduce the protein's helicase activity (Coin et al., 1998). In contrast, the TTD mutations usually fall outside of the helicase domains, and show significant clustering at the C-terminus of the protein. TTD-specific mutations may subtly interfere with the ability of XPD to interact with its partner proteins within the TFIIH complex, and thereby destabilize the complex (Coin et al., 1998). It has been argued that TTD mutations cause subtle deficiencies in transcription, because of reduced stability of TFIIH (de Boer et al., 1998a; Hoeijmakers et al., 1996). Alternatively, the TTD mutations affect the recruitment of the TFIIH complex to cyclobutane dimers, but not to [6-4] photoproducts (Chigancas et al., 2008).
XPE (DDB1/DDB2)
The XPE complementation group includes patients who are mildly to moderately affected and whose cells carry out near normal levels of NER (Itoh et al., 2000). Since excision repair is close to normal in XPE cells, a definitive diagnosis of XPE requires sequencing of the XPE gene (DDB2) to identify mutations (Cleaver et al., 1999; Itoh et al., 2000, 2001; Nichols et al., 1996).
The XPE group involves mutations in one component of a dimeric protein having subunits of 127 kDa (DDB1) and 48 kDa (DDB2) (Chu and Chang, 1988; Keeney et al., 1993; Nichols et al., 1996, 2001). The DDB1 and DDB2 genes are located on chromosome 11q12-13 and 11p11-12, respectively (Dualan et al., 1995). Mutations diagnostic for XPE patients are located in the DDB2 subunit, and cells without such mutations should be assigned to other groups after further diagnosis (Cleaver et al., 1999; Itoh et al., 2000, 2001; Nichols et al., 1996). The DDB1/2 heterodimer is thought to be involved with the recognition of damaged DNA, because it has the capacity to bind to UV-damaged DNA (Chu and Chang, 1988) with a chemically defined footprint on both DNA strands (Reardon et al., 1993).
Figure 6. Location of the mutations in the XPE (DDB2) gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Figure reproduced from Rapic-Otrin, V., et al. Hum. Mol. Genet 12:1507-1522, 2003, with permission of Oxford University Press.
The role of DDB1/2 in the pathway of excision repair appears to be in the early recognition of a damaged site, and the subsequent activation of XPC/HR23B binding, and consequently the suppression of UV mutagenesis (Tang et al., 2000).
DDB2 expression is induced by UV radiation through p53 transactivation in human, but not mouse, cells (Nichols et al., 2001; Tang and Chu, 2002). This provides a partial explanation for observations that the excision repair of cyclobutane dimers is low in some mouse cell strains.
XPF (ERCC4)
The XPF complementation group is rare, and the majority of cases have been found in Japan. Although the majority of patients have a mild photosensitive phenotype, mouse Xpf strains are very severely affected (Tian et al., 2004), suggesting that many mutations in XPF are inconsistent with viability, and only mild mutations permit human survival and development (Niedernhofer et al., 2006). XPF is located on chromosome 16p13.3, and encodes a structure-specific endonuclease of 916 amino acids, which in association with the ERCC1 protein (de Laat et al., 1998), incises DNA on the 5' side of the damaged site (Bessho et al., 1997; Niedernhofer et al., 2004; Sijbers et al., 1996, 1998).
Figure 7. Location of the mutations in the XPF gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Matsumura et al Human Molecular Genetics 7:969-974, 1998, with permission of Oxford University Press.
XPG (ERCC5)
XPG is located on chromosome 13q32-33, and encodes an 1186 amino acid nuclease, which incises DNA 3' to the damaged site (Nouspikel and Clarkson, 1994; O'Donovan et al., 1994). The gene is also known as ERCC5. The XPG complementation group is rare, and most cases are known from Europe. Patients are severely affected, and often exhibit combined symptoms of XP and CS (Nouspikel et al., 1997). These combined symptoms have been used to reveal a second function for XPG in the repair of oxidative damage (Nouspikel et al., 1997).
Figure 8. Location of mutations in the XPG gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Scharer, XPG: its products and biological roles, in Molecular mechanisms of xeroderma pigmentosum, Chapter 9, 2008, with permission from Landes Bioscience.
XP-Variant
XP-V patients present with a similar clinical spectrum to those of XP-C patients, but were found to have normal excision repair, but abnormal replication of damaged DNA (Cleaver, 1972; Lehmann et al., 1975). XPV is located on chromosome 6p21, and encodes a protein of 713 amino acids (Johnson et al., 1999; Masutani et al., 1999). The protein is a low-fidelity class Y DNA polymerase, variously known as hRad30A, pol eta or Pol H (Ohmori et al., 2001). The complete human genomic sequence spans about 40kb containing 10 coding exons and a cDNA of 2.14kb; exon I is untranslated and is 6kb upstream from the first coding exon (Cleaver et al., 2003; Thakur et al., 2001). Pol H can replicate UV-induced pyrimidine dimers in vivo with the insertion of the correct bases in the daughter strand; in vitro it is very error-prone and inserts mutagenic bases at about 1% frequency (Johnson et al., 2000; Matsuda et al., 2000; Ohashi et al., 2000).
Figure 9. Location of the mutations in the XPV gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Broughton et al., Proc Natl Acad Sci USA 99: 815-820, 2002, with permission from the National Academy of Sciences USA.
CSA (ERCC8)
CSA is located on chromosome 5, and encodes a 396 amino acid WD repeat protein that is involved in the coupling between transcription and repair (Henning et al., 1995). The gene is also known as ERCC8. Cells with mutations in CSA fail to ubiquitinate RNA polymerase II after UV exposure (Bregman et al., 1996), and cannot remove and degrade the transcription complex stalled at a damaged site in DNA. The arrest of Pol II at damaged sites has been suggested as the most specific damage recognition process (Lindsey-Boltz and Sancar, 2007). The predominance of neurological and developmental disorders in CS patients suggests that CSA and CSB (see below) play a role in repair of endogenous DNA damage, probably oxidative reactions in neural tissue (Cleaver and Revet, 2008; Frosina, 2008).
Several lines of evidence support the idea that inadequate repair of endogenous damage may be the cause of CS neurodegeneration (see below for CSB). The capacity for oxidative damage repair is reduced in CSA cells but to a lesser extent than in CSB (D'Errico et al., 2007).
Figure 10. Location of the mutations in the CSA gene. CSA protein and amino acid changes caused by the mutations detected in nine patients with Cockayne syndrome. The diagram shows the CSA protein with the putative WD repeats (red boxes). The amino acid changes are shown boxed. The numbers 1 and 2 after the patient code denote the different alleles. Patient code in blue: CS classical form; patient code in black: CS severe form, patient code in grey: CS severity not specified. Reproduced from Stefanini and Ruggieri, Cockayne syndrome. Chapter 52: 793-820, 2008, in Neurocutaneous Disorders with permission of Springer-Verlag.
CSB (ERCC6)
CSB is located on chromosome 10q11-21, and encodes a 1493 amino acid protein with helicase motifs, and is also involved in the coupling between repair and transcription. The gene is also known as ERCC6. Cells with mutations in CSB also fail to ubiquitinate RNA polymerase II, and cannot remove and degrade the transcription complex stalled at a damaged site in DNA (Bregman et al., 1996). The protein has a nucleotide binding site, and acts as a DNA-dependent ATPase, but despite the helicase motifs at the sequence level, the protein does not appear to possess helicase activity in vitro (Citterio et al., 1998; Selby and Sancar, 1997a; Selby and Sancar, 1997b). Mutations in CSB can give rise to a wide range of symptoms ranging from mild UV sensitivity (Horibata et al., 2004) to the severe neonatal lethal disorder, COFS (Laugel et al., 2008b), but a specific correlation between the site of mutation and the clinical severity has not yet been made.
Figure 11. Location of the mutations in the CSB gene. This illustration is typical of a large number of mutations in this gene, but not necessarily all that have been reported. Reproduced from Mallery et al., American Journal of Human Genetics 62:77-85, 1998, with the addition of the UVs and exon 1 mutations and the site of PGBD3 in intron 5, with permission from the American Society of Human Genetics, University of Chicago Press.
A transposon, PGBD3 ("PiggyBac"-like) has been identified within intron 5 of the CSB gene, which functions as an alternative 39nt terminal exon (Newman et al., 2008). The alternatively spliced mRNA encodes an abundant chimeric protein in which CSB exons 2-5 are joined in frame to the PiggyBac transposase in a variety of human cell lines (exon 1 is untranslated). This chimeric protein continues to be expressed in primary CS cells in which functional CSB is lost due to mutations beyond exon 5. The CSB-transposase fusion protein has been highly conserved for at least 43 Myr, since the divergence of humans and marmoset, but is not found in rodents. The suggestion has been made that this protein may cause CS in the absence of functional CSB protein, but this is unlikely for several reasons. CSB mutations are found both 3' and 5' to the intron 5 transposon (Figure 11), and mice with the Csb or Csa homolog knocked out give Cockayne-like disorders despite the absence of the transposon in rodents. The presence of the fusion protein is also not correlated with the severity of CSB symptoms (Laugel et al., 2008a).
The predominance of neurological and developmental disorders in CS patients suggests that CSB plays a role in the repair of endogenous oxidative DNA damage, originating most probably in mitochondria (Cleaver and Revet, 2008; Frosina, 2008). CSB mutant cells are sensitive to a variety of oxidants, and are unable to react to hypoxic stimuli by properly activating the hypoxia-inducible factor-1 (HIF-1) pathway (Filippi et al., 2008). CSB expression is under the control of HIF-1, and redistributes p300 between HIF-1 and p53 during hypoxic response (Filippi et al., 2008).
UV Sensitive Patients For Whom Genetic Defects Remain Uncharacterized
Some UV-sensitive patients have provided cell lines that are UV sensitive and show normal excision repair and a failure of RNA synthesis to recover from UV damage, even though the patients do not have the typical characteristics of CS patients (Cleaver et al., 1992; Fujiwara et al., 1981). These have been defined as the UVs syndrome (Fujiwara et al., 1981). Complementation assays and DNA sequencing have shown that some of these represent unusual manifestations of mutations in the known XP or CS genes, but others appear to genuinely different (Itoh et al., 1994, 1995).
One case of UVs was found to have a termination mutation in the early region of the CSB gene resulting in an apparent absence of the CSB protein (Horibata et al., 2004). Two other CSB patients have been reported, however, with a 5' deletion of the noncoding exon I and upstream sequences in CSB, and a similar complete lack of protein (Laugel et al., 2008a). These cases show extremely severe CS symptoms, inconsistent with the prediction from the UVs case (Horibata et al., 2004). The apparent lack of protein in the one UVs case with a CSB mutation cannot, therefore, be the sole cause of the mild symptoms. One possible explanation is that certain sequence contexts permit a small amount of gene translation through termination codons, producing low levels of protein undetectable by western blots. Some UVs cases are sensitive to UV radiation, but not to oxidative damage (Spivak and Hanawalt, 2006), suggesting that low levels of protein may be sufficient for the repair of oxidative damage, but not UV damage.
Patient Care And Treatment
Clinical care for repair deficient diseases has concentrated on prevention and treatment of skin cancers (Lambert et al., 2006). The neurological and other symptoms present a much greater a greater challenge (Cleaver and Revet, 2008).
For all of the photosensitive diseases, the paramount approach is early diagnosis and stringent protection from sun exposure (Cleaver, 2008; Lambert et al., 2006). While this approach is difficult and is not perfect, it does reduce the rate of onset of skin symptoms, including cancers. The development of skin cancers can be treated with a variety of approaches, including 5-fluorouracil and imiquimod creams (Lambert et al., 2006). Retinoids have been used with some success, but there can be unacceptable side effects on bone strength (Kraemer et al., 1992; Lambert et al., 2006). Surgical excision of tumors may also be necessary, but due to the high frequency with which new tumors arise, considerable disfigurement may result, and metastatic disease may eventually occur.
Several gene therapy approaches have been attempted with XP. Yarosh and colleagues have developed a DNA repair cream that delivers bacterial repair genes to the skin with some considerable success (Yarosh et al., 2001). Delivering corrected genes has also shown success in model systems, but in patients the difficulty would be in treating the whole area of sun-exposed skin (Armelini et al., 2005; Arnaudeau-Begard C et al., 2003; Marchetto et al., 2005).
Since a common belief attributes neurodegeneration to cellular damage from reactive oxygen, treatment with antioxidants could be one approach (Heidrick et al., 1984; Holloszy, 1998; Meydani et al., 1998). Treatment of Atm mice, which are deficient in the double-strand break responses, with antioxidants has shown promising success in reducing Purkinje cell damage, and improving behavioral endpoints (Chen et al., 2003; Gueven et al., 2006), and this could be attempted in Cs and Xp mice. A complication in using knockout mice, however, is that many NER-deficient mice show milder neurodegenerative symptoms than human, and the cancer burden higher, especially for Csa, Csb (Laposa et al., 2007; van der Horst et al., 1997, 2002) and Xpa (Berg et al., 1997; De Vries, 1997; Tanaka et al., 2001).
A major regulatory problem regarding clinical trials in human repair deficient patients is that there are too few patients with whom to design safety and effectiveness trials. One possibility would be to test drugs and antioxidants that have already been approved by the U.S. Food and Drug Administration for use in Alzheimers, Parkinson's and other more common neurological disorders.
Internet Links
Xeroderma pigmentosum
Xeroderma Pigmentosum Society
XP Family Support Group
Cockayne Syndrome
Cockayne Syndrome Network
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