The human TFIIH complex. Eight of the ten TFIIH subunits are recognizable in this structure. The structural model was made with PyMOL using the published data (PDB accession number: 5OF4). TFIIH, transcription factor IIH.
Recruitment and functions of TFIIH in GG-NER. XPC binds to the damage site first. The interaction between XPC and TFIIH subunits p62 and XPB leads to the recruitment of TFIIH. XPA removes the CAK kinase module, which activates the helicase function of the TFIIH core complex to conduct DNA unwinding and damage verification. GG-NER, global genome NER; TFIIH, transcription factor IIH.
Recruitment and potential functions of TFIIH in TC-NER. The p62 subunit of TFIIH physically interacts with UVSSA and the interaction facilitates TFIIH recruitment to the damage-stalled RNA Pol II. Pol II ubiquitylation at Lys1268 enhances binding of TFIIH to Pol II. As DNA around the lesion is melted by RNA Pol II, the recruited TFIIH potentially extends the transcription bubble to generate a full-sized repair bubble. Similar to GG-NER, TFIIH may also verify the presence of a bulky lesion. However, it is unclear to what extent TC-NER requires TFIIH鈥檚 damage verification function, because RNA Pol II stalling may play a redundant role. Another potential role for TFIIH is to help Pol II backtracking or displacement. TC-NER, transcription-coupled NER; TFIIH, transcription factor IIH.
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Abstract
News — DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair mechanisms are a fundamental part of life. Nucleotide excision repair (NER) plays an important role in the removal of bulky DNA adducts, such as cyclobutane pyrimidine dimers from ultraviolet light or DNA crosslinking damage from platinum-based chemotherapeutics, such as cisplatin. A main component for the NER pathway is transcription factor IIH (TFIIH), a multifunctional, 10-subunit protein complex with crucial roles in both transcription and NER. In transcription, TFIIH is a component of the pre-initiation complex and is important for promoter opening and the phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH is important for DNA unwinding, recruitment of downstream repair factors, and verification of the bulky lesion. Several different disease states can arise from mutations within subunits of the TFIIH complex. Most strikingly are xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD). Here, we summarize the recruitment and functions of TFIIH in the two NER subpathways, global genomic (GG-NER) and transcription-coupled NER (TC-NER). We will also discuss how TFIIH's roles in the two subpathways lead to different genetic disorders.
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Caption: The human TFIIH complex. Eight of the ten TFIIH subunits are recognizable in this structure. The structural model was made with PyMOL using the published data (PDB accession number: 5OF4). TFIIH, transcription factor IIH.
Credit:
Caption: Recruitment and functions of TFIIH in GG-NER. XPC binds to the damage site first. The interaction between XPC and TFIIH subunits p62 and XPB leads to the recruitment of TFIIH. XPA removes the CAK kinase module, which activates the helicase function of the TFIIH core complex to conduct DNA unwinding and damage verification. GG-NER, global genome NER; TFIIH, transcription factor IIH.
Credit:
Caption: Recruitment and potential functions of TFIIH in TC-NER. The p62 subunit of TFIIH physically interacts with UVSSA and the interaction facilitates TFIIH recruitment to the damage-stalled RNA Pol II. Pol II ubiquitylation at Lys1268 enhances binding of TFIIH to Pol II. As DNA around the lesion is melted by RNA Pol II, the recruited TFIIH potentially extends the transcription bubble to generate a full-sized repair bubble. Similar to GG-NER, TFIIH may also verify the presence of a bulky lesion. However, it is unclear to what extent TC-NER requires TFIIH鈥檚 damage verification function, because RNA Pol II stalling may play a redundant role. Another potential role for TFIIH is to help Pol II backtracking or displacement. TC-NER, transcription-coupled NER; TFIIH, transcription factor IIH.
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Environmental and Molecular Mutagenesis
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