Transcription factor II H

Transcription Factor II H (TFIIH) is a multifunctional protein complex essential in several critical cellular processes, including transcription, nucleotide excision repair (NER), and cell cycle regulation. It plays a pivotal role in the transcription of genes by RNA polymerase II, a process fundamental for the synthesis of messenger RNA (mRNA) in eukaryotic cells. Additionally, TFIIH is involved in DNA repair mechanisms, specifically in the repair of DNA damage caused by ultraviolet (UV) radiation.

Composition and Structure

TFIIH consists of ten subunits, divided into two sub-complexes: the Core complex and the CAK (CDK-activating kinase) complex. The Core complex includes subunits such as XPB and XPD, which are helicases responsible for unwinding DNA, and p62, p52, p44, p34, and TTDA. The CAK complex, which is involved in cell cycle control, includes CDK7, cyclin H, and MAT1. The intricate structure of TFIIH allows it to engage in various interactions necessary for its diverse functions.

Function in Transcription

During transcription initiation, TFIIH is recruited to the promoter region of a gene as part of the pre-initiation complex (PIC). The helicase activity of TFIIH unwinds the DNA, allowing RNA polymerase II to access the template strand. Furthermore, the kinase activity of the CAK complex phosphorylates the C-terminal domain (CTD) of RNA polymerase II, a modification crucial for the transition from transcription initiation to elongation.

Role in DNA Repair

TFIIH's involvement in nucleotide excision repair (NER) highlights its critical role in maintaining genomic integrity. In NER, TFIIH unwinds the DNA around a lesion, such as a thymine dimer caused by UV light, enabling the excision of the damaged strand and subsequent repair. Mutations in TFIIH subunits, particularly in XPB and XPD, are linked to rare genetic disorders like Xeroderma Pigmentosum and Cockayne Syndrome, which are characterized by sensitivity to UV light and increased risk of skin cancer.

Cell Cycle Regulation

The CAK complex of TFIIH also influences the cell cycle by phosphorylating several key proteins, including CDKs (cyclin-dependent kinases), which are vital for cell cycle progression. This regulatory function underscores the importance of TFIIH beyond transcription and DNA repair, highlighting its role in cell proliferation and growth.

Clinical Significance

Given its essential functions, TFIIH is a target of interest in the study of cancer and other diseases where transcription, DNA repair, and cell cycle regulation are disrupted. Understanding the mechanisms of TFIIH action and its interactions with other cellular components may lead to novel therapeutic strategies for treating such conditions.

Research and Future Directions

Ongoing research aims to elucidate the detailed mechanisms by which TFIIH functions in its various roles and to understand how mutations in TFIIH components contribute to disease. Advances in structural biology techniques, such as cryo-electron microscopy, have provided insights into the architecture of TFIIH and its interactions within the cell, offering potential avenues for drug development.