TFIIH

TFIIH is a conserved, multi-subunit protein complex essential for two fundamental cellular processes: transcription initiation by RNA polymerase II and nucleotide excision repair (NER). In eukaryotes, TFIIH exists as a core complex and a regulatory kinase module, collectively forming holo-TFIIH when associated.

The core TFIIH contains two crucial DNA helicases, XPB and XPD, along with several smaller subunits that stabilize the complex and coordinate its activities in transcription and repair. The regulatory subunit module, the CDK-activating kinase (CAK) module, comprises CDK7, Cyclin H, and MAT1. The CAK module can associate with the core TFIIH to form holo-TFIIH, providing CDK7 kinase activity that phosphorylates targets such as the RNA polymerase II C-terminal domain (CTD) during transcription initiation.

In transcription, TFIIH is recruited to the promoter as part of the preinitiation complex. XPB helicase activity aids in promoter DNA opening, enabling RNA polymerase II to initiate transcription. CDK7-mediated phosphorylation of the CTD at Ser5 facilitates promoter escape and the transition to productive elongation, as well as recruitment of RNA processing factors.

In nucleotide excision repair, TFIIH contributes to damage verification and the unwinding of DNA around bulky lesions. XPB and XPD helicases drive DNA opening, coordinating with other NER factors such as XPA, XPF-ERCC1, and XPG to excise damaged DNA and restore genome integrity.

Clinical significance is high: mutations in TFIIH subunits cause disorders including xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Due to its dual roles, TFIIH remains a focus in studies of transcription regulation and DNA repair, with CAK activity also explored as a potential target in cancer therapy.

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