Transcription-repair coupling factors

Selby, C.P. and Sancar, A. (1995) Structure and function of transcription-repair coupling factor. I. Structural domains and binding properties. 

Smith, A.J. and Savery, N.J. (2008) Effects of the bacterial transcription-repair coupling factor during transcription of DNA containing non-bulky lesions. DNA Repair, 7, 1670-1679. 

Transcription stimulates excision repair both in E. coli (Mellon and Hanawalt, 1989) and in humans (Bohr et al., 1985 Mellon et at, 1987) in a process dependent on proteins called transcription-repair coupling factors (TRCFs). In E. coli the mfd gene encodes the TRCF (Selby and Sancar, 1991,1993 Selby etaZ., 1991), and cells mutated in this gene exhibit modest UV sensitivity but a disproportionately increased rate of UV-induced mutations and lack of mutation frequency decline (mfd) on holding in minimal medium after irradiation and before plating (Witkin, 1994). 

Fig. 5. Model for transcription-coupled repair in E. coli. A lesion in the nontranscribed (NT) strand has no effect on RNA polymerase (RNAP) (left side), but a lesion in the transcribed strand blocks progression of RNAP (right). Transcription-repair coupling factor (TRCF) recognizes and binds to the stalled...

Park, J.-S., Marr, M. T., and Roberts, J. W. (2002). E. coli transcription repair coupling factor (Mfd protein) rescues arrested complexes by promoting forward translocation. Cell 109, 757-767. 

Washburn, R. S., Wang, Y., and Gottesman, M. E. (2003). Role of E. coli transcription-repair coupling factor Mfd in Nun-mediated transcription termination./. Mol. Biol. 329, 655-662. 

Lesions in transcription units pose three fundamental problems for the cell (i) they can permit an RNA polymerase to bypass with limited or no detectable pausing, but alter the nascent RNA, (ii) they can pause or transiently stall elongation, slowing transcription, or (iii) they can pose absolute blocks to elongation. In all these cases, the role of elongation factors, DNA repair, and documented or putative transcription-DNA repair coupling factors may well modulate these outcomes. Figure 17.7 illustrates these possibilities. 

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. 

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.0 Like their yeast counterparts (proteins RAD3 and RAD25), XPB and XPD are both DNA helicases.0 They also constitute distinct subunits of the human transcription factor TFIIHP, which is discussed in Chapter 28. It seems likely that XPD is involved in transcription-coupled repair (TCR) of DNA.° °i-s 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 protein synthesis. Transcription-coupled repair also appears to depend upon proteins CSA and CSB, defects which may result in the rare cockayne syndrome.13 0 4 11 Patients are not only photosensitive but have severe mental and physical retardation including skeletal defects and a wizened appearance. 

As mentioned above, one consequence of stalled RNA polymerase II at a DNA adduct is activation of transcription-coupled repair [27], This effect may depend on the type of polymerase, however, since the removal of some types of DNA damage is slower from RNA-polymerase I transcribed ribosomal DNA than from a nuclear gene [160], The lower level of repair in the nucleolus could also reflect the influence of other transcription factors, such as the HMG-domain protein UBF, which bind to cisplatin-mod-ified DNA [145]. When HeLa cells were exposed to cisplatin at concentrations which did not seem to affect nuclear transcription, inhibition of rDNA gene expression was associated with the redistribution of UBF, along with other factors responsible for rRNA transcription [138], These observations indicate how cisplatin might exert a combination of effects. Transcription is stopped due to titration of essential factors by the platinum-DNA adducts, and the same proteins could shield the lesions from the repair activity. 

Hamrick SE, McQmllen PS, Jiang X, Mu D, Madan A, Ferriero DM (2005) A role for hypoxia-indudble factor-lalpha in desferoxamine neuroprotection. Neurosci Lett 379 96-100 Hanawalt PC (1994) Transcription-coupled repair and human disease. Science 266 1957-1958 Hayashi T, Abe K (2004) Ischemic neuronal cell death and oiganeUe damage. Neinol Res 26 827-834... 

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