GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy

Am J Hum Genet. 2016 Apr 7;98(4):627-42. doi: 10.1016/j.ajhg.2016.02.008.

Christiane Kuschal ¹, Elena Botta ², Donata Orioli ², John J Digiovanna ¹, Sara Seneca ³, Kathelijn Keymolen ³, Deborah Tamura ¹, Elizabeth Heller ¹, Sikandar G Khan ¹, Giuseppina Caligiuri ², Manuela Lanzafame ², Tiziana Nardo ², Roberta Ricotti ², Fiorenzo A Peverali ², Robert Stephens ⁴, Yongmei Zhao ⁵, Alan R Lehmann ⁶, Laura Baranello ⁷, David Levens ⁷, Kenneth H Kraemer ⁸, Miria Stefanini ⁹

Affiliations

1 Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
2 Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy.
3 Center for Medical Genetics, Research Group Reproduction and Genetics, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
4 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.
5 Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
6 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
7 Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
8 Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: kraemerk@nih.gov.
9 Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address: stefanini@igm.cnr.it.

PMID: 26996949 DOI: 10.1016/j.ajhg.2016.02.008

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.