TFIIH transcription/repair factor

Svjestrup, Q., Vichi,P. and Egli,J.-M. The multiple roles of transcription/repair factor TFIIH (1996) Trends Biochem.Sd. 71, 346-350... 

Park, C.H., Mu, D., Reardon, J.T., and Sancar, A. (1995) The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor. /. Biol. Chem., 270, 4896-4902. 

Egly,J.-M. (2001). TFIIH From transcription to clinic. FEES Lett. 24884, 124-128. Evans, E., Moggs,J. G., Hwang, J. R., Egly,J.-M., and Wood, R. D. (1997). Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBOJ. 16, 6559-6573. 

The discovery of the involvement of a transcription factor in excision repair was prompted by the observation by Bohr et al. (1985) that excision-repair was differentiated between fast repair coupled with transcription and a slower mode observed in non-transcribing regions of DNA. One of the human genes, XPC, is required only for the latter mode of repair. Its homologue, RAD4 in yeast, where similar differentiation has been observed, is found to associate with the TFIIH complex, suggesting that these proteins may be involved in associating the complex specifically with inactive chromatin. 

Chang, W.H. and Kornberg, R.D. (2000) Electron crystal structure of the transcription factor and DNA repair complex, core TFIIH. Cell, 102, 609-613. 

Egly, J.M. (1993) DNA repair helicase a component of BTF2 (TFIIH) basic transcription factor. Science, 260, 58-63. 

Remarkably, five polypeptide subunits of TFIIH, a general transcription factor, are required for nucleotide excision repair in eukaryotic cells, including two with homology to hellcases, as shown in Figure 23-30. In transcription, the helicase activity of TFIIH unwinds the DNA helix at the start site, allowing RNA polymerase II to begin (see Figure 11-27). It appears that nature has used a similar protein assembly in two different cellular processes that require helicase activity. 

While defects in protein XPD often cause typical XP symptoms, some defects in the same protein lead to trichothiodystrophy (TTD, brittle hair disease). The hair is sulfur deficient, and scaly skin (ichthyosis, Box 8-F), mental retardation, and other symptoms are observed. Like their yeast coimterparts (proteins RADS and RAD25), XPB and XPD are both DNA helicases. They also constitute distinct subunits of the human transcription factor TFIIH , which is discussed in Chapter 28. It seems likely that XPD is involved in transcription-coupled repair (TCR) of DNA. This is a subpathway of the nucleotide excision repair (NER) pathway, which allows for rapid repair of the transcribed strand of DNA. This is important in tissues such as skin, where the global NER process may be too slow to keep up with the need for rapid profein synthesis. Transcription-coupled repair also appears to depend upon proteins CSA and CSB, defects which may result in the rare cocka3me s5mdrome. Patients are not only photosensitive but have severe mental and physical retardation including skeletal defects and a wizened appearance. 

TFIIH plays a number of roles in both transcription and DNA repair. In both processes, it acts as an ATP-dependent DNA helicase, unwinding DNA for either transcription or repair to occur. Two of the forms of xeroderma pigmentosum (XPB and XPD see Chapter 13) arise from mutations within two different helicase subunits of TFIIH. TFIIH also contains a kinase activity, and RNA polymerase II is phos-phorylated by this factor during certain phases of transcription. 

Its primary function is as a general transcription factor involved in the formation of the open complex for transcription initiation. It binds to the basal unit and is involved in DNA melting through a helicase activity as well as promoter clearance via phosphorylation of the CTD of RNA polymerase. In addition, it also has a cyclin-dependent kinase activity. Thus, TFIIH is involved in tying transcription and cell division together. It is also involved in DNA repair mechanisms. 

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