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Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH
Author(s) -
Coin Frédéric,
Bergmann Etienne,
TremeauBravard Alexandre,
Egly JeanMarc
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.5.1357
Subject(s) - xeroderma pigmentosum , transcription factor ii h , biology , helicase , genetics , transcription (linguistics) , nucleotide excision repair , dna , dna repair , gene , rna , linguistics , philosophy
As part of TFIIH, XPB and XPD helicases have been shown to play a role in nucleotide excision repair (NER). Mutations in these subunits are associated with three genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The strong heterogeneous clinical features observed in these patients cannot be explained by defects in NER alone. We decided to look at the transcriptional activity of TFIIH from cell lines of XP individuals. We set up an immunopurification procedure to isolate purified TFIIH from patient cell extracts. We demonstrated that mutations in two XP‐B/CS patients decrease the transcriptional activity of the corresponding TFIIH by preventing promoter opening. The defect of XPB in transcription can be circumvented by artificial opening of the promoter. Western blot analysis and enzymatic assays indicate that XPD mutations affect the stoichiometric composition of TFIIH due to a weakness in the interaction between XPD–CAK complex and the core TFIIH, resulting in a partial reduction of transcription activity. This work, in addition to clarifying the role of the various TFIIH subunits, supports the current hypothesis that XP‐B/D patients are more likely to suffer from transcription repair syndromes rather than DNA repair disorders alone.