In vivo interactions of TTDA mutant proteins within TFIIH

Nonnekens, Julie; Cabantous, Stéphanie; Slingerland, Joris; Mari, Pierre-Olivier; Giglia-Mari, Giuseppina

doi:10.1242/jcs.126839

Cited by 15 publications

(22 citation statements)

References 23 publications

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“…As we have not performed TTDA protein analysis, we cannot verify the formation of TTDA proteins truncated by 24% and there is another possibility of no TTDA expression by nonsense‐mediated TTDA mRNA decay. However, each of the abnormalities may be related to the various symptoms of TTD noted in the present patient because mutant p8 proteins (L21P and R56X) have been reported to not interact with p52, resulting in a reduced quantity of TFIIH and a mutant p8 protein (E55X) similar to R56X bearing p8 protein is thought to not function normally.…”

Section: Discussionmentioning

confidence: 83%

“…The photosensitive type of TTD is mutated in XPB , XPD and GTF2H5 (a gene for TTDA/p8), three of the units of TFIIH, which functions as a transcription factor and recruits to the site of UV‐induced DNA damage, resulting in subsequent steps of NER: opening, incision and excision. An 8‐kDa protein is important for maintaining UV irradiation resistance and is essential for NER and transcription …”

Section: Discussionmentioning

confidence: 99%

“…An 8-kDa protein is important for maintaining UV irradiation resistance 9 and is essential for NER and transcription. 10,11 Thus far, only one Japanese TTD patient, who exhibited compound heterozygous XPD mutations (c.2164C>T/del67-69), resulting in an amino acid change (R722W/S23del), has been reported. 7 We herein described the second TTD and first Japanese TTD-A patient with a novel homozygous GTF2H5 mutation.…”

Section: Discussionmentioning

confidence: 99%

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Trichothiodystrophy group A: A first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene

Moriwaki

Saruwatari

Kanzaki

et al. 2014

The Journal of Dermatology

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Trichothiodystrophy group A (TTD-A) is one of the three types of photosensitive TTD and is a very rare genodermatosis with deficient post-ultraviolet (UV) DNA repair. We herein describe the first Japanese case with a novel mutation in the GTF2H5 gene responsible for TTD-A. A 5-year-old male, born as a collodion baby from healthy non-consanguineous parents, exhibited sun sensitivity, brittle hair, ichthyosis, cataracts and mental/physical retardation. He demonstrated neither neurological abnormalities nor pigmentary changes following sun exposure. The patient's primary fibroblasts were hypersensitive to killing by UV (D 0 = 1.5 J/m 2 ), and the post-UV unscheduled DNA synthesis was 13% of normal. A host cell reactivation complementation analysis showed a decreased DNA capacity without recovery after transfecting any xeroderma pigmentosum genes. We identified a novel homozygous mutation (c.166G>T) in the coding region of the GTF2H5 gene that resulted in a predicted amino acid change: p.E55X. Thus far, only one Japanese case of TTD with a mutation of the XPD gene had been reported. The present case is the first of TTD-A and the second case of TTD in Japan, suggesting that it is necessary to differentiate TTD from other photosensitive disorders, although the incidence of TTD is very low in Japan compared to that observed in Western countries.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Trichothiodystrophy group A: A first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene

Moriwaki

Saruwatari

Kanzaki

et al. 2014

The Journal of Dermatology

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“…These data seem to be against the proposed role for p8 in maintaining TFIIH stability and in contrast to the observation of lower levels of the TFIIH subunits in human cells derived from patients, who suffer from TTD-A. However, the p8 mutations described in these patients seem not to be null, and it has recently been reported that they still may interact with TFIIH [14,34]. Thus, it is possible that these mutations may generate p8 proteins that have some toxic effect when they are assembled into TFIIH, generating instability in the complex.…”

Section: Discussionmentioning

confidence: 86%

Analysis ofDrosophila p8andp52mutants reveals distinct roles for the maintenance of TFIIH stability and male germ cell differentiation

Cruz‐Becerra¹,

Juárez²,

Valadéz-Graham³

et al. 2016

Open Biol.

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Eukaryotic gene expression is activated by factors that interact within complex machinery to initiate transcription. An important component of this machinery is the DNA repair/transcription factor TFIIH. Mutations in TFIIH result in three human syndromes: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Transcription and DNA repair defects have been linked to some clinical features of these syndromes. However, how mutations in TFIIH affect specific developmental programmes, allowing organisms to develop with particular phenotypes, is not well understood. Here, we show that mutations in the p52 and p8 subunits of TFIIH have a moderate effect on the gene expression programme in the Drosophila testis, causing germ cell differentiation arrest in meiosis, but no Polycomb enrichment at the promoter of the affected differentiation genes, supporting recent data that disagree with the current Polycomb-mediated repression model for regulating gene expression in the testis. Moreover, we found that TFIIH stability is not compromised in p8 subunit-depleted testes that show transcriptional defects, highlighting the role of p8 in transcription. Therefore, this study reveals how defects in TFIIH affect a specific cell differentiation programme and contributes to understanding the specific syndrome manifestations in TFIIH-afflicted patients.

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“…Overexpressing TTDA in a DNA repair deficient human XP-D cells [22] or in a p52 Drosophila melanogaster mutant (Dmp52, which exhibits TTD and cancer-like phenotypes in the fly [23]), partly restored TFIIH levels and/or NER defects. Finally, a novel tripartite split-GFP system confirmed binding of TTDA to p52 in living human cells [24].…”

Section: Characterization Of Ttdamentioning

confidence: 81%