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GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2016 Apr 07; Vol. 98 (4), pp. 627-42. Date of Electronic Publication: 2016 Mar 17. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Cyclin-Dependent Kinases metabolism
DNA Damage
DNA Helicases genetics
DNA Helicases metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Female
Gene Silencing
Humans
Infant
Male
Molecular Sequence Data
Mutation, Missense
Pedigree
Phosphorylation
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Transcription Factor TFIIH genetics
Transcription Factor TFIIH metabolism
Transcription Factors, TFII metabolism
Xeroderma Pigmentosum Group D Protein genetics
Xeroderma Pigmentosum Group D Protein metabolism
Cyclin-Dependent Kinase-Activating Kinase
Cyclin-Dependent Kinases genetics
DNA Repair
Transcription Factors, TFII genetics
Trichothiodystrophy Syndromes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 98
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26996949
- Full Text :
- https://doi.org/10.1016/j.ajhg.2016.02.008