The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases.

DNA, the genetic material in all living organisms, is continually exposed to agents that cause damage to its structure, resulting in the loss of vital genetic information. To counteract the potentially devastating effects of such damage, all organisms have evolved a series of different repair processes, with which many kinds of damage to the DNA can be corrected. The importance of DNA repair is shown by the existence of several human genetic disorders that are caused by defects in one of these repair processes. Thus, for example, most individuals with xeroderma pigmentosum (XP) are unable to repair damage generated in DNA by ultraviolet (UV) light from the sun, whereas patients with hereditary nonpolyposis colon carcinoma are defective in the repair of mismatched bases. XP was the first DNA-repair disorder to be identified. It is a rare autosomal recessive genetic disorder characterized by numerous skin abnormalities ranging from excessive freckling to multiple skin cancers (Fig. 1a) (Bootsma et al. 1998). The incidence of skin cancer is about 2000-fold greater than in normal individuals. All skin abnormalities result from exposure to sunlight and are caused by inability to repair DNA damage induced in the skin by sunlight. The more severely affected patients have neurological abnormalities caused by premature neuronal death. Cells from XP donors are hypersensitive to killing by UV irradiation, and this is caused, in the majority of cases, by defects in nucleotide excision repair (NER), the process with which UV-induced photoproducts in the DNA are removed and replaced (Friedberg et al. 1995). XP is genetically heterogeneous. There are eight complementation groups designated XP-A through G and XP-variant. The XPD gene, defective in XP individuals assigned to the XP-D complementation group, is the topic of this review.

[1]  J. Hoeijmakers,et al.  Engagement with transcription , 1993, Nature.

[2]  A. Bailis,et al.  The essential helicase gene RAD3 suppresses short-sequence recombination in Saccharomyces cerevisiae , 1995, Molecular and cellular biology.

[3]  A. Lehmann,et al.  Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity. , 1998, American journal of human genetics.

[4]  J. Bradsher,et al.  p44/SSL1, the Regulatory Subunit of the XPD/RAD3 Helicase, Plays a Crucial Role in the Transcriptional Activity of TFIIH* , 2000, The Journal of Biological Chemistry.

[5]  P. Hanawalt,et al.  Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay. , 1997, Biochimica et biophysica acta.

[6]  D. Moras,et al.  Molecular Structure of Human TFIIH , 2000, Cell.

[7]  D. Reinberg,et al.  Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II , 1994, Nature.

[8]  F. Holstege,et al.  Opening of an RNA polymerase II promoter occurs in two distinct steps and requires the basal transcription factors IIE and IIH. , 1996, The EMBO journal.

[9]  A. Sarasin,et al.  Recovery of normal DNA repair and mutagenesis in trichothiodystrophy cells after transduction of the XPD human gene. , 1996, Cancer research.

[10]  L. Thompson,et al.  Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. , 1995, Cancer research.

[11]  P. Itin,et al.  Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias. , 1990, Journal of the American Academy of Dermatology.

[12]  S. Squires,et al.  The XPD complementation group. Insights into xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. , 1992, Mutation research.

[13]  J. Hoeijmakers,et al.  Cancer from the outside, aging from the inside: mouse models to study the consequences of defective nucleotide excision repair. , 1999, Biochimie.

[14]  J. Hurwitz,et al.  Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Green,et al.  The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect. , 2000, Cancer research.

[16]  U. Vogel,et al.  Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[17]  P. Sung,et al.  Mutation of lysine‐48 to arginine in the yeast RAD3 protein abolishes its ATPase and DNA helicase activities but not the ability to bind ATP. , 1988, The EMBO journal.

[18]  Wei-Hau Chang,et al.  Electron Crystal Structure of the Transcription Factor and DNA Repair Complex, Core TFIIH , 2000, Cell.

[19]  B. Montelone,et al.  Analysis of the rad3‐101 and rad3‐102 mutations of saccharomyces cerevisiae: Implications for structure/function of rad3 protein , 1994, Yeast.

[20]  R. Wood,et al.  TFIIH with Inactive XPD Helicase Functions in Transcription Initiation but Is Defective in DNA Repair* , 2000, The Journal of Biological Chemistry.

[21]  S. Giliani,et al.  Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. , 1993, Carcinogenesis.

[22]  L. Thompson,et al.  Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. , 1996, American journal of human genetics.

[23]  P. Sung,et al.  RAD3 protein of Saccharomyces cerevisiae is a DNA helicase. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[24]  I. M. Jones,et al.  Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. , 1998, Cancer research.

[25]  R. Wood,et al.  Mechanism of open complex and dual incision formation by human nucleotide excision repair factors , 1997, The EMBO journal.

[26]  S. Humbert,et al.  Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH). , 1994, The EMBO journal.

[27]  L. Thompson,et al.  ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3. , 1990, The EMBO journal.

[28]  F. Tirode,et al.  Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. , 1999, Molecular cell.

[29]  J. Hoeijmakers,et al.  Nucleotide excision repair. II: From yeast to mammals. , 1993, Trends in genetics : TIG.

[30]  L. Prakash,et al.  Isolation and characterization of the RAD3 gene of Saccharomyces cerevisiae and inviability of rad3 deletion mutants. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Chambon,et al.  DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. , 1993, Science.

[32]  D. Tomescu,et al.  Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. , 2001, Carcinogenesis.

[33]  C. Rodolfo,et al.  Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH , 1998, Nature Genetics.

[34]  K. Kinzler,et al.  The Genetic Basis of Human Cancer , 1997 .

[35]  R. Wood,et al.  UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP‐D and Cockayne syndrome , 2000, The EMBO journal.

[36]  R. Tarone,et al.  The Oxidative DNA Lesion 8,5′-(S)-Cyclo-2′-deoxyadenosine Is Repaired by the Nucleotide Excision Repair Pathway and Blocks Gene Expression in Mammalian Cells* , 2000, The Journal of Biological Chemistry.

[37]  J. Hoeijmakers,et al.  Molecular and cellular analysis of the DNA repair defect in a patient in xeroderma pigmentosum complementation group D who has the clinical features of xeroderma pigmentosum and Cockayne syndrome. , 1995, American journal of human genetics.

[38]  H. Steingrimsdottir,et al.  Five polymorphisms in the coding sequence of the xeroderma pigmentosum group D gene. , 1996, Mutation research.

[39]  J. Egly,et al.  Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH , 1999, The EMBO journal.

[40]  P. Sung,et al.  Human xeroderma pigmentosum group D gene encodes a DMA helicase , 1993, Nature.

[41]  D. Mitchell,et al.  Relationship between pyrimidine dimers, 6-4 photoproducts, repair synthesis and cell survival: studies using cells from patients with trichothiodystrophy. , 1990, Mutation research.

[42]  P. Hanawalt,et al.  Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis. , 2000, Molecular cell.

[43]  M. Nance,et al.  Cockayne syndrome: review of 140 cases. , 1992, American journal of medical genetics.

[44]  F. Holstege,et al.  Three transitions in the RNA polymerase II transcription complex during initiation , 1997, The EMBO journal.

[45]  R. Parshad,et al.  XPD polymorphisms: effects on DNA repair proficiency. , 2000, Carcinogenesis.

[46]  J. Hoeijmakers,et al.  A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. , 1998, Molecular cell.

[47]  S. Giliani,et al.  DNA repair investigations in nine Italian patients affected by trichothiodystrophy. , 1992, Mutation research.

[48]  Y. Nakatsu,et al.  Mutations in the XPD gene leading to xeroderma pigmentosum symptoms , 1997, Human mutation.

[49]  L. Naumovski,et al.  A DNA repair gene required for the incision of damaged DNA is essential for viability in Saccharomyces cerevisiae. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Bardwell,et al.  Dual roles of a multiprotein complex from S. cerevisiae in transcription and DNA repair , 1993, Cell.

[51]  D. Reinberg,et al.  Human cyclin-dependent kinase-activating kinase exists in three distinct complexes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[52]  D. Garfinkel,et al.  Nucleotide Excision Repair/TFIIH Helicases Rad3 and Ssl2 Inhibit Short-Sequence Recombination and Ty1 Retrotransposition by Similar Mechanisms , 2000, Molecular and Cellular Biology.

[53]  A. Lehmann,et al.  Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[54]  T. Lindahl,et al.  Removal of oxygen free-radical-induced 5',8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  J. Garssen,et al.  Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. , 1999, Cancer research.

[56]  J. Hoeijmakers,et al.  The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. , 1994, The EMBO journal.

[57]  J. Hoeijmakers,et al.  Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality. , 1998, Cancer research.

[58]  H. Steingrimsdottir,et al.  Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy , 1994, Nature Genetics.

[59]  J. Dupuy,et al.  [Photosensitization and DNA repair. Possible nosologic relationship between Xeroderma pigmentosum and Cockayne's syndrome]. , 1978, Archives francaises de pediatrie.

[60]  J. Hoeijmakers,et al.  Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases. , 1995, Cancer research.

[61]  L. Mullenders,et al.  Cells from XP-D and XP-D-CS patients exhibit equally inefficient repair of UV-induced damage in transcribed genes but different capacity to recover UV-inhibited transcription. , 1999, Nucleic acids research.

[62]  L. Mullenders,et al.  Deficient repair of the transcribed strand of active genes in Cockayne's syndrome cells. , 1993, Nucleic acids research.