Transcription factor IIH (TFIIH) complex (TFIIH)

The Transcription factor IIH (TFIIH) complex is a multi-subunit protein assembly essential for two fundamental cellular processes: RNA polymerase II-mediated transcription and nucleotide excision repair (NER) (Compe & Egly, 2012, PMID: 22444420). It is composed of ten subunits organized into a core complex (XPB, XPD, p62, p52, p44, p34, and p8) and a CDK-activating kinase (CAK) module (CDK7, Cyclin H, and MAT1) (Rimel & Taatjes, 2018, PMID: 29681501). During transcription initiation, the XPB subunit utilizes its ATPase activity to facilitate DNA promoter melting, while the CDK7 subunit phosphorylates the C-terminal domain of RNA polymerase II to trigger the transition to elongation (Sainsbury et al., 2015, PMID: 25913191). In the NER pathway, the XPB and XPD helicases work together to unwind the DNA double helix around a lesion, allowing for the removal of damaged nucleotides (Kuper & Kisker, 2017, PMID: 28429314). Mutations in TFIIH subunits are linked to severe genetic disorders such as Xeroderma pigmentosum, Cockayne syndrome, and Trichothiodystrophy (DiGiovanna & Kraemer, 2012, PMID: 22273738). In oncology, TFIIH is a target of interest because many tumors exhibit transcriptional addiction; inhibitors like triptolide (targeting XPB) and THZ1 (targeting CDK7) have shown potent anti-tumor activity by disrupting these essential processes (Titov et al., 2011, PMID: 21454756; Kwiatkowski et al., 2014, PMID: 24906153). Therapeutic development focuses on balancing these potent anti-tumor effects with the potential for systemic toxicity given the complex's fundamental role in all eukaryotic cells.

Other names

General transcription factor IIHBTF2Basic transcription factor 2TFIIH core complexHolocomplex TFIIH

Inhibition of XPB (ERCC3) ATPase/helicase activity, degradation of the XPB subunit, or covalent inhibition of the CDK7 subunit kinase activity to block transcription and DNA repair (Titov et al., 2011, PMID: 21454756; Kwiatkowski et al., 2014, PMID: 24906153).