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.

Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue

“…Recently, two unrelated NPS-TTD patients were identified with different mutations in the gene encoding for the beta subunit of transcription initiation factor II E ( TFIIEβ/GF2E2 ) ( 14 ), suggesting impaired transcription in these patients. To provide functional evidence for affected transcription in NPS-TTD, we first performed genetic analyses among a selected group of NPS-TTD patients to identify possible other mutations in transcription factors.…”

“…We hypothesize that a large of part of the clinical features associated with repair-proficient non-photosensitive TTD (NPS-TTD) are based on gene expression defects ( 12 ). In only a minority of NPS-TTD patients causative mutations were found in genes encoding for the M-phase-specific PLK1 interacting protein ( MPLKIP/TTDN1 ) ( 13 ) or the β subunit of the transcription factor IIE ( GTF2E2/TFIIEβ ) ( 14 ) and in an isolated case in the RNF113A gene ( 15 ). Nevertheless, thus far no obvious experimental evidence for transcription malfunctioning in NPS-TTD patient cells has been provided.…”

Genetic profile and biological implication of PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) in human cancers: an analysis using The Cancer Genome Atlas

“…GTF2E2 is also named general transcription factor IIE (TFIIE), which is part of the RNA polymerase II transcription initiation complex. It recruits TFIIH and is essential for promoter clearance by RNA polymerase II [ 26 ]. INTS10 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit and mediates 3-prime end processing of small nuclear RNAs U1 and U2 [ 27 ].…”

Mortality‐associated immunological abnormalities in trichothiodystrophy: correlation of reduced levels of immunoglobulin and neutrophils with poor patient survival

“…Trichothiodystrophy (TTD) is a rare, autosomal recessive disease characterized by a low content of sulphur‐rich proteins in hair (Liang et al , ; DiGiovanna & Kraemer, ). Causative mutations described for TTD have been found in the genes ERCC2 (previously termed XPD ), ERCC3 (also termed XPB ), and GTF2H5 (subunits of the TFIIH basal transcription factor complex involved in transcription and nucleotide excision repair; also termed TTDA ), GTF2E2 (a subunit of the TFIIE transcription factor complex that recruits TFIIH to the RNA polymerase II transcription initiation complex) and MPLKIP (M‐phase specific PLK1 interacting protein; also termed TTDN1 ) (Kuschal et al , ).…”