Dataset Information

Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.

ABSTRACT: Trichothiodystrophy (TTD) is a rare autosomal premature-ageing and neuroectodermal disease. The photohypersensitive form of TTD is caused by inherited mutations in three of the 10 subunits of the basal transcription factor TFIIH. TFIIH is an essential transcription initiation factor that is also pivotal for nucleotide excision repair (NER). Photosensitive TTD is explained by deficient NER, dedicated to removing UV-induced DNA lesions. TTD group A (TTD-A) patients carry mutations in the smallest TFIIH subunit, TTDA, which is an 8-kDa protein that dynamically interacts with TFIIH. TTD-A patients display a relatively mild TTD phenotype, and TTD-A primary fibroblasts exhibit moderate UV sensitivity despite a rather low level of UV-induced unscheduled DNA synthesis (UDS). To investigate the rationale of this seeming discrepancy, we studied the repair kinetics and the binding kinetics of TFIIH downstream NER factors to damaged sites in TTD-A cells. Our results show that TTD-A cells do repair UV lesions, although with reduced efficiency, and that the binding of downstream NER factors on damaged DNA is not completely abolished but only retarded. We conclude that in TTD-A cells repair is not fully compromised but only delayed, and we present a model that explains the relatively mild photosensitive phenotype observed in TTD-A patients.

SUBMITTER: Theil AF

PROVIDER: S-EPMC3165551 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.

Theil Arjan F AF Nonnekens Julie J Wijgers Nils N Vermeulen Wim W Giglia-Mari Giuseppina G Giglia-Mari Giuseppina G

Molecular and cellular biology 20110705 17

Trichothiodystrophy (TTD) is a rare autosomal premature-ageing and neuroectodermal disease. The photohypersensitive form of TTD is caused by inherited mutations in three of the 10 subunits of the basal transcription factor TFIIH. TFIIH is an essential transcription initiation factor that is also pivotal for nucleotide excision repair (NER). Photosensitive TTD is explained by deficient NER, dedicated to removing UV-induced DNA lesions. TTD group A (TTD-A) patients carry mutations in the smallest ...[more]

PMID: 21730288

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Project description:The incorporation of ribonucleotides in DNA has attracted considerable notice in recent years, since the pool of ribonucleotides can exceed that of the deoxyribonucleotides by at least 10-20-fold, and single ribonucleotide incorporation by DNA polymerases appears to be a common event. Moreover ribonucleotides are potentially mutagenic and lead to genome instability. As a consequence, errantly incorporated ribonucleotides are rapidly repaired in a process dependent upon RNase H enzymes. On the other hand, global genomic nucleotide excision repair (NER) in prokaryotes and eukaryotes removes damage caused by covalent modifications that typically distort and destabilize DNA through the production of lesions derived from bulky chemical carcinogens, such as polycyclic aromatic hydrocarbon metabolites, or via crosslinking. However, a recent study challenges this lesion-recognition paradigm. The work of Vaisman et al. (2013) [34] reveals that even a single ribonucleotide embedded in a deoxyribonucleotide duplex is recognized by the bacterial NER machinery in vitro. In their report, the authors show that spontaneous mutagenesis promoted by a steric-gate pol V mutant increases in uvrA, uvrB, or uvrC strains lacking rnhB (encoding RNase HII) and to a greater extent in an NER-deficient strain lacking both RNase HI and RNase HII. Using purified UvrA, UvrB, and UvrC proteins in in vitro assays they show that despite causing little distortion, a single ribonucleotide embedded in a DNA duplex is recognized and doubly-incised by the NER complex. We present the hypothesis to explain the recognition and/or verification of this small lesion, that the critical 2'-OH of the ribonucleotide - with its unique electrostatic and hydrogen bonding properties - may act as a signal through interactions with amino acid residues of the prokaryotic NER complex that are not possible with DNA. Such a mechanism might also be relevant if it were demonstrated that the eukaryotic NER machinery likewise incises an embedded ribonucleotide in DNA.

Dataset Information

Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.

Publications

Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts.

Similar Datasets

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