The Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to -Cockayne Syndrome-Like Phenotypes

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TFIIH is a protein complex that functions in the repair of bulky adducts distorting the DNA via the pathway of Nucleotide Excision Repair, and in transcription initiation and transactivation, the latter being a specific transcription activation process occurring in response to hormones. We have taken advantage of the powerful genetics and molecular biology of the model organism Saccharomyces cerevisiae to characterize the impact on cell fitness of a particular kind of mutations of one of the two helicases of the TFIIH complex, Rad3, called rem mutations for their increased levels of recombination and mutation. We have realized that these mutations affect a particular site of the protein, its ATP-binding groove, and modify the dynamics of TFIIH, leading to unfinished repair reactions and DNA break accumulation. Finally, we recreated these mutations in the human homolog XPD protein and found that their phenotypes recapitulated those of human mutations leading to a combination of the two hereditary diseases Xeroderma pigmentosum and Cockayne syndrome (XP-D/CS), whose molecular basis remains elusive. As these mutations also affect the ATP-binding groove of XPD, this study permits to propose a model to explain the molecular basis of XP-D/CS.

Vyšlo v časopise: The Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to -Cockayne Syndrome-Like Phenotypes. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004859
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004859

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