3. TFIIH Mutations, Diseases/Disorders and Potential Therapeutic Opportunities
Due to the crucial role of TFIIH in NER, germline mutations in TFIIH subunits have been linked with human disorders, including XP, XP in combination with CS (XP/CS), and Trichothiodystrophy (TTD) (Coin et al., 1998; Lehmann, 2001; Rapin et al., 2000). Most of the pathogenic TFIIH germline mutations occur in the XPD subunit. Of note, many of the mutations within the XPD protein that lead to the XP, XP/CS, and TTD disease states are found towards the end of the protein (Table 1 ), in the final helicase residues and the p44 binding domain (Lehmann, 2001). Furthermore, somatic mutations in TFIIH, particularly mutations in the XPD subunit, have been widely observed in human cancers (Kim et al., 2016). Somatic mutations in XPD can presumably increase genome instability and promote tumorigenesis. On the other hand, mutations in XPD represent potential vulnerability of tumor cells that can be targeted by treatment with DNA damaging agents, such as platinum-based chemotherapy, thus providing an important opportunity to treat these tumors (Q. Li et al., 2019).