title: GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.
abstract: The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEβ). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEα and TFIIEβ) as well as decreased phosphorylation of TFIIEα in cells from both children. Interestingly, decreased phosphorylation of TFIIEα was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP.
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuschal
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Botta
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Donata
authors.initials: D
authors.lastname: Orioli
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Digiovanna
authors.affiliation: Center for Medical Genetics, Research Group Reproduction and Genetics, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Seneca
authors.affiliation: Center for Medical Genetics, Research Group Reproduction and Genetics, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Keymolen
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Tamura
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Heller
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Sikandar G
authors.initials: SG
authors.lastname: Khan
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caligiuri
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lanzafame
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricotti
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Fiorenzo A
authors.initials: FA
authors.lastname: Peverali
authors.affiliation: Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA; Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Stephens
authors.affiliation: Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Baranello
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.affiliation: Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: kraemerk@nih.gov.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kraemer
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address: stefanini@igm.cnr.it.
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
mesh_terms: D000595:Amino Acid Sequence; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH / Q000235:genetics / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000235:genetics* / Q000378:metabolism; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D019473:Transcription Factors, TFII; C066644:transcription factor TFIIE; C072022:XPBC-ERCC-3 protein; D051758:Transcription Factor TFIIH; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D000095043:Cyclin-Dependent Kinase-Activating Kinase