Introduction

Among the most prominent DNA-damaging agents, the ultraviolet (UV) spectrum of sunlight induces lesions in DNA that may alter the genetic information and lead to genomic instability and carcinogenesis. To eliminate DNA damage, an extremely accurate system of complementary DNA-repair mechanisms has evolved (1). A defect in any of these repair pathways reveals their biological importance in counteracting DNA damage. The consequences of defective repair of UV-induced DNA damage are depicted in three rare autosomal recessive photosensitive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and the photosensitive form of the brittle hair disease trichothiodystrophy (TTD) (2).

XP is a human hereditary disorder with a cancer-prone phenotype that is genetically heterogeneous, and in most cases (but not all) results from defective nu-cleotide excision repair (NER) of DNA damage (2,3). Cell fusion experiments have defined seven different genetic XP complementation groups that are defective in NER and are referred to as XP-A through XP-G. The eighth group, called the XP-V (variant) group, is deficient in the ability to replicate DNA containing UV pho-toproducts. With the exception of XP-V, all the proteins defective in groups XP-A to XP-G are components of the NER pathway and include three damage-recognition proteins (XPA, XPC, and XPE), two helicases (XPB and XPD), and two nucleases (XPG and XPF). XPB and XPD are part of the basal transcription factor TFIIH that is required for NER and initiation of transcription by RNA polymerase

Figure 1 Involvement of different XP proteins in NER. The figure shows the role of each XP protein in the different steps of NER. Damage is recognized by XPC in GGR, or stalled transcription complexes and the CSA and CSB proteins in TCR. TFIIH is recruited and forms an open complex. XPG and XPA/RPA are then recruited and position XPG and XPF/ERCC1 on either side of the damage, resulting in incision of the DNA on both sides of the damage. (Modified from Ref. 27.)

Figure 1 Involvement of different XP proteins in NER. The figure shows the role of each XP protein in the different steps of NER. Damage is recognized by XPC in GGR, or stalled transcription complexes and the CSA and CSB proteins in TCR. TFIIH is recruited and forms an open complex. XPG and XPA/RPA are then recruited and position XPG and XPF/ERCC1 on either side of the damage, resulting in incision of the DNA on both sides of the damage. (Modified from Ref. 27.)

II (4). Because of this dual role of TFIIH, mutations in the two helicase subunits can affect both NER and transcription and thereby give rise to XP-associated syndromes, such as the combined clinical phenotype of XP/CS and TTD. The features of CS and TTD are quite different from those of XP and are thought to result from impaired transcription activity (4). In contrast to the other seven XP complementation groups, XP-V cells show normal NER activity, but they are deficient in a postreplication repair-translesion synthesis pathway (5,6). Cloning of the XPV gene has shown that it encodes a novel DNA polymerase, pol^, which is able to synthesize DNA past UV damage (7,8).

NER is a major DNA defense mechanism against the carcinogenic effects of sunlight. It removes a wide range of helix-distorting lesions, such as UV-induced cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) photoprod-ucts (6-4 PPs), as well as bulky adducts induced by chemicals such as N-acetoxy-2-acetylaminofluorene (AAAF) and benzo[a]pyrene-diol epoxide.

NER requires the function of at least 30 polypeptides and consists of several sequential steps: (a) recognition of DNA damage, (b) local opening of the DNA helix around the lesion, (c) single-stranded incision on either side of the lesion, (d) excision of the damaged portion of the DNA strand, (e) DNA repair synthesis for filling in the resulting gap using the intact complementary strand as a template, and (f) ligation of the newly synthesized strand.

Two partly overlapping subpathways (Fig. 1) have been described for NER. The first subpathway, known as global genome repair (GGR), involves repair activity on DNA lesions across the whole genome; for the majority of the lesions, this activity is relatively slow. The second subpathway is coupled to active transcription and eliminates lesions from the transcribed strand of active genes that block ongoing transcription. The latter pathway is termed transcription-coupled repair (TCR). As shown in Figure 1, it is the initial damage-recognition step that differs between the two pathways, whereas subsequent steps use the same mechanism. For GGR, the XPC/HR23B complex detects the damage and recruits the repair machinery, whereas in TCR, stalled RNA polymerase II and possibly the CSA and CSB proteins (specifically required for TCR and defective in patients with CS) are the damage-recognition signal for the recruitment of the NER machinery.

This chapter will describe the variable clinical features of XP and the roles of the XP gene products in the NER and postreplication repair processes.

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