XP is a rare autosomal recessive disorder characterised by dry, flaking skin (xeroderma), abnormal pigmentation on sun exposed areas of the skin (pigmentosum), photosensitivity and a marked predisposition (1000-2000x that of general population) to all forms of skin cancer (reviewed in [6-8]).  Some of the most severely affected XP individuals also exhibit associated growth defects and neurological abnormalities arising from neuron degeneration.

     Cell fusion studies have identified at least eight XP complementation groups (i.e. mutations in any one of (at least) eight separate genes result in XP).  One of these, XP-variant (XP-V), is deficient in the error-free replicational bypass of damaged DNA, the result of mutations in the gene encoding DNA polymerase h [9-12]. The remaining seven ("classical") XP groups (labelled XP-A through XP-G) all exhibit deficiencies in nucleotide excision repair.  Each of the complementation groups exhibits a defect in the global genome repair (GGR) aspect of NER, and while this is often accompanied by a corresponding defect in the transcription coupled repair (TCR)  sub-pathway, there are exceptions (see Table II).

     Cells from XP groups A, B, D and G are characterised by general defects in NER which affect both GGR and TCR of UV-induced damage.  However, cells from XP group C can efficiently repair actively transcribed genes, in spite of a severe deficiency in the repair of inactive DNA [13-16].  XP-F cells are defective in both TCR [16, 17], and the GGR of 6-4 PP [18, 19] but curiously retain GGR of CPD [16, 19].  Cells from XP-E individuals have been characterised with proficient TCR [20] and slow (but ultimately complete) repair of 6-4PP [19-22].  Reports of repair of CPD from the bulk of the genome in XP-E cells ranges from slow and/or impaired to indistinguishable from normal [17-21].  Consistent with only a modest repair defect, individuals belonging to group E exhibit the mildest clinical symptoms of the XP groups.
 

     Clinically, CS is primarily a developmental disorder (reviewed in [6-8]).  It is characterised by profound physical and mental retardation, progressive pigmentary retinopathy, characteristic wizened facies with sunken eyes, a thin prominent nose, and the appearance of premature ageing.  Neurological abnormalities include delayed psychomotor development and microcephaly, arising from decreased myelination in both the central and peripheral nervous systems, and from the accumulation of calcium deposits in the brain.  Like XP, CS is also associated with UV sensitivity, however it is not associated with skin cancer.
 Most CS patients fall into two complementation groups CS-A and CS-B.  In spite of the associated UV-sensitivity, early assays of these cells did not reveal a deficiency in the ability to repair UV-induced DNA damage [23, 24].  However, the observation that CS cells were deficient in the recovery of RNA synthesis following cellular exposure to UV [3], and improved assaying techniques, revealed that CS cells are specifically deficient in the preferential repair of UV damage in active genes (i.e. TCR), although they retain proficient GGR [4, 25].  The UV-sensitivity exhibited by CS individuals is likely a result of the accumulation of damage in active genes, which is a signal for the induction of apoptosis (a programmed cell-death mechanism -- essentially cell-suicide) [26].  Such a predisposition towards the induction of apoptosis would be expected to be protective against the development of skin cancer as cells are eliminated before they can acquire sufficient damage to accumulate mutations.

     It is difficult to attribute the severe developmental abnormalities of CS solely to a defect in the TCR sub-pathway of NER, particularly when many XP patients completely deficient in both NER pathways (GGR as well as TCR) display a considerably milder clinical presentation.  One possible explanation for this apparent paradox arises from the demonstration that CS cells exhibit a defect in the TCR of oxidative damage [27, 28], as well as TCR of UV-C induced DNA damage.  As oxidative damage is repaired by the base excision repair pathway, this suggests that the proteins which are defective in CS function in a TCR subpathway of base excision repair as well as that of NER.  This in turn suggests that the developmental abnormalities of CS result from the inability to efficiently remove oxidative damage (accumulating due to the high metabolic rate of developing embryonic cells) from active genes.

     Although XP and CS are clinically distinct syndromes, some overlap between the two has been observed.  A few individuals falling into the XP groups B [29, 30], D [31-33] and G [34] exhibit symptoms of CS in addition to those of XP.  Cells from individuals comprising this XP/CS complex have provided additional means for examining the molecular defect responsible for CS symptoms.  Like CS cells, a deficiency in the repair of oxidative damage has been demonstrated for XP-G/CS cells, while cells from XP-G individuals (not demonstrating symptoms of CS) retain proficient repair of this damage [28, 35, 36].  However, unlike CS cells, the defect in repair of oxidative DNA damage in XP-G/CS cells is evident in inactive as well as transcriptionally active DNA [28].

     The identification of the XPD and XPB gene products as components of the RNA polymerase II (RNA pol II) transcription factor TFIIH [37-39] and the association of the CSB protein with the elongating RNA pol II complex [40-42] has led to the suggestion that the clinical symptoms of CS arise from a primary defect in transcription.  Such a defect would be expected to affect the transcription-dependent TCR pathway, as well as accounting for the array of developmental abnormalities.  However, the CS proteins do not appear to be essential for basal transcription [40], but rather in the cellular ability to recover RNA synthesis following treatment with DNA damaging agents [40, 43].  Similarly, extracts from CS and XPB/CS cells exhibit impaired in vitro transcription of substrates containing oxidative damage, but not undamaged DNA [44].  Furthermore, although XP-D and XP-D/CS cells repair damage in active genes at similar rates, XP-D/CS cells exhibit a significant delay in the ability to restore RNA synthesis relative to XP-D cells [45].  This is consistent with an inability to reinitiate or continue transcription from RNA pol II complexes stalled at the sites of DNA damage.
 
 

      Individuals with TTD (reviewed in [6-8]) are marked by sulphur-deficient brittle hair that is dry, sparse and easily broken.  Other symptoms include impaired physical and mental development, a peculiar face, and ichthyosis (scaly, fish-like skin) [46].  UV-sensitivity is also associated with approximately 50% of TTD cases [5], although (like CS) this is not associated with a predisposition towards the development of skin cancers.  Interestingly, the molecular defect in almost all (90%) of the photosensitive TTD patients is attributable to mutations in the same gene as that for XP-D [47, 48].  Defects in the remaining photosensitive TTD patients are attributed to mutations in the XPB gene [49] and to a third (as yet unidentified) component of the transcription factor TFIIH [50].

     In spite of an early report to the contrary [51], it appears that the primary NER defect in photosensitive TTD individuals results in aberrant repair of CPD, while 6-4 PP are repaired at near normal levels [52, 53].  As a result of considerable heterogeneity in the severity of the NER defect in TTD cells [51, 52, 54], they have been subdivided into three classes based on UV-sensitivity and the nature of the NER defect [52].  The first class is comprised of non-photosensitive patients, who exhibit normal repair of both CPD and 6-4PP.  The second class is characterised by moderate UV sensitivity, and defective repair of CPD (generally 20-40%) but normal repair of 6-4PP.  The third class is very UV-sensitive and exhibits defective repair of CPD (<15%) as well as reduced repair of 6-4 PP (55-70%).  TTD cells (and murine cells carrying an equivalent mutation) have also been reported to exhibit some deficiency in TCR [55]. 

      Interestingly, the clinical presentation of TTD bears considerable resemblance to that of CS (see Table I), with the addition of hair and skin problems.  Furthermore, the occurrence of (class I) TTD in the absence of a detectable NER defect, and the association of mutations in TFIIH with TTD has led to speculation that the primary defect in TTD may also be one of transcription, rather than repair.  According to this model [8] the transcription defect in TTD patients becomes particularly evident in differentiated keratinoctes (producing hair and cornified envelope) resulting in the cardinal features of brittle hair and ichthyosis.
 

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