The cryo-electron microscopy structure of human transcription factor IIH

Abstract

The cryo-electron microscopy structure of the ten-subunit human transcription factor IIH, revealing the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Transcription factor IIH (TFIIH) is part of the general transcriptional machinery required to initiate eukaryotic gene transcription by RNA polymerase II (Pol II). TFIIH is also required for nucleotide excision DNA repair, and mutations in certain subunits occur in human genetic diseases. Here, Eva Nogales and colleagues have determined a cryo-electron microscopy structure of the 10-subunit human TFIIH, revealing an architecture dominated by the two ATPase subunits XPB and XPD. Disease-linked mutations can be mapped onto the structure. Comparisons between the structure of free TFIIH and that of TFIIH complexed with the Pol II pre-initiation complex provide initial insight into conformational rearrangements and a further step towards a complete mechanistic understanding of transcription initiation. Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription1. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair1. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair2, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation1,2. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology3. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.