Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy.

Trichothiodystrophy (TTD) is a rare hereditary multisystem disorder associated with defects in nucleotide excision repair (NER) as a consequence of mutations in XPD, XPB or TTDA, three genes that are all related to TFIIH, the multiprotein complex involved in NER and transcription. Here we show that all the mutations found in TTD cases, irrespective of whether they are homozygotes, hemizygotes or compound heterozygotes, cause a substantial and specific reduction (by up to 70%) in the cellular concentration of TFIIH. Intriguingly, the degree of reduction in the level of TFIIH does not correlate with the severity of the pathological phenotype, suggesting that the severity of the clinical features in TTD cannot be related solely to the effects of mutations on the stability of TFIIH. We have also measured TFIIH levels in cells in which different mutations in the XPD gene are associated with clinical symptoms not of TTD but of the highly cancer-prone disorder xeroderma pigmentosum (XP). We have found mild reductions (up to 40%) in TFIIH content in some but not all of these cell strains. We conclude that the severity of the clinical features in TTD patients and the clinical outcome of differentially mutated XPD proteins is likely to depend both on the effects that each mutation has on the stability of TFIIH and on the transcriptional activity of the residual TFIIH complexes.

[1]  C. Arlett,et al.  Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity , 1986, Human Genetics.

[2]  V. Lamour,et al.  p52 Mediates XPB Function within the Transcription/Repair Factor TFIIH* 210 , 2002, The Journal of Biological Chemistry.

[3]  A. Sarasin,et al.  XPD Mutations Prevent TFIIH-Dependent Transactivation by Nuclear Receptors and Phosphorylation of RARα , 2002, Cell.

[4]  C. Cancrini,et al.  Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia , 2001, Clinical and experimental immunology.

[5]  J. Tolmie,et al.  Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. , 2001, Human molecular genetics.

[6]  A. Lehmann,et al.  Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene. , 2001, Human molecular genetics.

[7]  J. Graham,et al.  Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. , 2001, American journal of human genetics.

[8]  Shwu‐Yuan Wu,et al.  Reconstitution of recombinant TFIIH that can mediate activator‐dependent transcription , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[9]  J. Egly,et al.  A Role of the C-terminal Part of p44 in the Promoter Escape Activity of Transcription Factor IIH* , 2001, The Journal of Biological Chemistry.

[10]  J. Egly,et al.  Trichothiodystrophy, a transcription syndrome. , 2001, Trends in genetics : TIG.

[11]  A. M. Pedrini,et al.  Different dynamics in nuclear entry of subunits of the repair/transcription factor TFIIH. , 2001, Nucleic acids research.

[12]  J. Hoeijmakers,et al.  A temperature-sensitive disorder in basal transcription and DNA repair in humans , 2001, Nature Genetics.

[13]  D. Reinberg,et al.  Defective Interplay of Activators and Repressors with TFIIH in Xeroderma Pigmentosum , 2001, Cell.

[14]  A. Lehmann,et al.  The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. , 2001, Genes & development.

[15]  J. Hoeijmakers,et al.  Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder , 2000, Nature Genetics.

[16]  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.

[17]  P. Chambon,et al.  TFIIH Interacts with the Retinoic Acid Receptor γ and Phosphorylates Its AF-1-activating Domain through cdk7* , 2000, The Journal of Biological Chemistry.

[18]  Simak Ali,et al.  Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. , 2000, Molecular cell.

[19]  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.

[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]  H. Pospiech,et al.  Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. , 2000, Genes & development.

[22]  Q. Waisfisz,et al.  A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  O. Nikaido,et al.  The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. , 1999, Human molecular genetics.

[24]  P. Jeggo,et al.  The C Terminus of Ku80 Activates the DNA-Dependent Protein Kinase Catalytic Subunit , 1999, Molecular and Cellular Biology.

[25]  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.

[26]  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.

[27]  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.

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

[29]  J. Egly,et al.  Ten years of TFIIH. , 1998, Cold Spring Harbor symposia on quantitative biology.

[30]  G. Orphanides,et al.  The RNA polymerase II general transcription factors: past, present, and future. , 1998, Cold Spring Harbor symposia on quantitative biology.

[31]  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.

[32]  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.

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

[34]  J. Hoeijmakers,et al.  A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. , 1997, American journal of human genetics.

[35]  P. J. van der Spek,et al.  Mutational analysis of the human nucleotide excision repair gene ERCC1. , 1996, Nucleic acids research.

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

[37]  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.

[38]  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.

[39]  E. Friedberg,et al.  Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. , 1994, Human molecular genetics.

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

[41]  R. Roeder,et al.  Regulation of TFIIH ATPase and kinase activities by TFIIE during active initiation complex formation , 1994, Nature.

[42]  R. Scott,et al.  Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3. , 1994, American journal of human genetics.

[43]  W. Vermeulen,et al.  Three unusual repair deficiencies associated with transcription factor BTF2(TFIIH): evidence for the existence of a transcription syndrome. , 1994, Cold Spring Harbor symposia on quantitative biology.

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

[45]  S. Giliani,et al.  A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. , 1993, American journal of human genetics.

[46]  J. Hoeijmakers,et al.  DNA repair. Engagement with transcription. , 1993, Nature.

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

[48]  E. Berardesca,et al.  Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy , 1992, Clinical and experimental immunology.

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

[50]  S. Giliani,et al.  Xeroderma pigmentosum complementation group H falls into complementation group D. , 1991, Mutation research.

[51]  H. Steingrimsdottir,et al.  Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. , 1988, Cancer research.