Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG

Abstract

Alterations in genes involved in nucleotide excision repair (NER) are associated with three genetic disorders, xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The transcription and repair factor TFIIH is a central component of NER and mutations of its subunits are associated with all three diseases. A recent report provides a molecular basis for how mutations in the NER endonuclease XPG that affect the interaction of TFIIH might give rise to CS features. In cells of XP-G patients with a combined XP and CS phenotype, XPG fails to associate with TFIIH and as a consequence the CAK subunit dissociates from core TFIIH. A simplified, but general model of how various assembly and disassembly states of TFIIH can be invoked to explain different disease states is discussed. Accordingly, defects in specific enzymatic functions typically result in XP, dissociation of the CAK subunit from TFIIH is associated with XP/CS and a more generalized destabilization of TFIIH gives rise to TTD. While this classification provides a useful framework to understand how alterations in TFIIH correlate with disease states, it does not universally apply and relevant exception and alternative explanations are discussed.

Figure 1. Correlation of assembly and disease states in TFIIH

A. In wild-type cells TFIIH consists of 10 subunits; XPB, XPD, p62, p52, p44, p34 and p8 form the core (purple), the CAK subunit (orange) consisting of MAT1, cdk7 and cyclinH is linked through XPD. A fraction of XPG (blue) is constitutively associated with TFIIH. B. Mutations in XPD that affect its helicase activity and in XPG that affect its endonuclease activity, but not protein-protein interactions within TFIIH give rise to a XP phenotype. C. Mutations in XPD that disturb the interaction with p44 and in XPG that affect the interaction with the TFIIH core lead to the dissociation of the CAK subunit and combined XP/CS features. Certain XP-causing C-terminal mutations in XP-D also cause dissociation of the CAK subunit, but no CS symptoms. D. Mutations in TTD-A/p8 and XPD lead to an overall destabilization of TFIIH and result in a TTD phenotype. Similar destabilization of TFIIH and TTD-like phenotype is caused by a mutation in the Drosophila homolog of p52, Dpm52.