Repair, transcription-coupled

Excision repair is affected by other DNA transactions, including binding of regulatory proteins, compaction into chromatin, replication, recombination, and transcription. It has been found that transcription stimulates excision repair both in E. coli and in humans (Bohr et al, 1985 Mellon and Hanawalt, 1989 Mellon et al, 1987). Moreover, in the majority of cases, transcription stimulates the repair of only the transcribed strand (Mellon et al, 1987), and it may actually inhibit repair of the transcribed strand in the absence of an active mechanism coupling the two processes (Selby and Sancar, 1990). In the case of E. coli, the mechanism of transcription-coupled repair is reasonably well understood. In contrast, there is no in vitro system for eukaryotic transcription-coupled repair, and hence the mechanistic aspects of this process remain to be elucidated. 

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Verhage, R.A., van Gool, A.J., de Groot, N., Hoeijmakers, J.H., van de Putte, P., and Brouwer, J. (1996) Double mutants of Saccharomyces cerevisiae with alterations in global genome and transcription-coupled repair. Mol. Cell. Biol. 16, 496-502. 

Escargueil AE, Poindessous V, Soares DG Sarasin A, Cook PR, Larsen AK. (2008) Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells. J Cell Sci 121 1275-1283. 

Gowen, L.C., Avrutskaya, A.V., Latour, A.M., Roller, B.H. and Leadon, S.A. BRCAl required for transcription-coupled repair of oxidative DNA damage (1998) Science 281,1009-1012... 

Le Page F, Randrianarison V, Marot D et al. BRCAl and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res 2000 60 5548-5552. 

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. 

Wang G, Seidman MM, Glazer PM. Mutagenesis in mammalian cells induced by triple helix formation and transcription-coupled repair. Science 1996 271(5250) 802-5. 

Mellon, I. Transcription-coupled repair A complex affair. Mutat. Res. 577, 155-161, 2005. 

Hanawalt, P.C. (1994) Transcription-coupled repair and human disease. Science, 266, 1957-1958. 

Keywords Direct repair Base excision repair (BER) Nucleotide excision repair (NER) Transcription-coupled repair HR NHEJ DNA repair polymorphisms ... 

The NER pathway consists of two different sub-pathways known as global genome repair (GGR) and transcription-coupled repair (TCR). Most genes involved contribute to both sub-pathways. 

Ford JM, Hanawalt PC (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci USA 92 8876-80 Hwang BJ, Ford JM, Hanawalt PC, Chu G (1999) Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci USA 96 424-8... 

Cooper PK,Nouspikel T, Clarkson SG, Leadon SA (1997) Defective transcription-coupled repair of oxidative base damage in Cockayne syndrome patients from XP group G. Science 275 990-3... 

TFIIH also partidpates in another important cellular function, namely nucleotide excision repair of damaged DNA. This function accounts for the observation that transcription and the removal of bulky base adducts by nucleotide excision repair (NER) are coupled. An increased repair of DNA damage by NER is observed while a gene is being transcribed. During transcription-coupled repair, TFIIH assembles with other repair proteins into a large repair complex, allowing for the removal of DNA adducts. 

Islas, A.L., Baker, F.J., and Hanawalt, P.C. (1994) Transcription-coupled repair of psoralen cross-links but not monoadducts in Chinese hamster ovary cells. Biochemistry, 33,10794-10799. 

Recent studies of excision repair show that active genes (those undergoing transcription) are preferred substrates for excision repair, and within these genes the template DNA strand is preferentially repaired. Thus, the repair machinery is somehow directed toward sites where repair of DNA damage will do the most good. Transcription-coupled repair may initiate when a transcribing RNA polymerase stalls at the site of a DNA lesion. BRCA 1, a gene associated with increased risk of breast and ovarian cancer, has been implicated in transcription-coupled excision repair. 

BRCAl and BRCA2 also form a complex with protein RAD51, a RecA homolog necessary for homologous recombination. BRCAl also may be essential to transcription-coupled repair. ... 

Transcription-coupled repair proteins from XP family > ... 

Transcription-coupled repair. When RNA Pol II encounters a lesion, it stops translating. The polymerase must release or back up, while TFIIH (light purple) binds to the lesion and helps recruit the correct DNA repair enzymes. (Adapted by permission from Hanawalt,... 

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