Abstract
Mutations in certain subunits of the DNA repair/transcription factor complex TFIIH are linked to the human syndromes xeroderma pigmentosum (XP), Cockayne's syndrome (CS), and trichothiodystrophy (TTD). One of these subunits, p8/TTDA, interacts with p52 and XPD and is important in maintaining TFIIH stability. Drosophila mutants in the p52 (Dmp52) subunit exhibit phenotypic defects similar to those observed in TTD patients with defects in p8/TTDA and XPD, including reduced levels of TFIIH. Here, we demonstrate that several Dmp52 phenotypes, including lethality, developmental defects, and sterility, can be suppressed by p8/TTDA overexpression. TFIIH levels were also recovered in rescued flies. In addition, p8/TTDA overexpression suppressed a lethal allele of the Drosophila XPB homolog. Furthermore, transgenic flies overexpressing p8/TTDA were more resistant to UV irradiation than were wild-type flies, apparently because of enhanced efficiency of cyclobutane-pyrimidine-dimers and 6–4 pyrimidine-pyrimidone photoproducts repair. This study is the first using an intact higher-animal model to show that one subunit mutant can trans-complement another subunit in a multi-subunit complex linked to human diseases.
Highlights
The integrity of the DNA molecule can be disrupted by chemical and physical factors that cause diverse types of damage
We show that overexpression of Dmp8/TTDA can suppress a mutation in other TFIIH subunits and enhance UV-irradiation resistance in a living multicellular organism
An enabling observation and important motivation for this work is evidence that overexpression of the human p8/TTDA gene in human fibroblasts derived from patients with TTD caused by a mutation in the XPD gene can suppress some of the phenotypes observed in this cell line [8]
Summary
The integrity of the DNA molecule can be disrupted by chemical and physical factors that cause diverse types of damage. The subunits XPB, XPD, p62, p52, p44, p34, and p8 come together to form the core subcomplex of TFIIH, which preferentially participates in NER. The subunits cdk, cycH, and MAT1 form the cdk-activating kinase subcomplex (CAK), which is involved in controlling the cell cycle [2]. The core and CAK form the 10-protein TFIIH complex that has a fundamental role in RNA polymerase II (pol II) transcription [3]. The TFIIH complex possesses several enzymatic activities that contribute to NER, transcription, and cell cycle control: XPB and XPD, which are both ATPases and DNA helicases; cdk, which is a kinase; and p44, which is an ubiquitin ligase [2,4]. A characteristic of the cells derived from patients with TTD-A, and XPD-linked TTD, is a reduction in basal TFIIH levels [3]. XPB ATPase activity, which is required for NER, is modulated by the interaction of p8/ TTDA and p52 [10]. p8/TTDA exists in two different pools, one in PLoS Genetics | www.plosgenetics.org p8/TTDA Suppresses TFIIH Mutants
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