Cockayne s syndrome

When Pol II transcription halts at the site of a DNA lesion, TFIIH can interact with the lesion and recruit the entire nucleotide-excision repair complex. Genetic loss of certain TFIIH subunits can produce human diseases. Some examples are xeroderma pigmentosum (see Box 25-1) and Cockayne s syndrome, which is characterized by arrested growth, photosensitivity, and neurological disorders. ... 

FanconVs syndrome, a lethal aplastic anemia, is also due to defective DNA repair. Cells from alTected persons cannot repair interstrand cross-links or damage induced by x-rays. Two premature aging disorders (Hutchinson-Gilford syndrome and Bloom s syndrome) and several other disorders Cockayne s syndrome and retinoblastoma) are also associated with defects in DNA repair. Cells from patients with some chromosome abnormalities (e.g., Down syndrome) may also show aberrant DNA repair. 

Another approach that has been used to probe the functions of the polymer involves the study of repair deficient cell lines. Cell lines derived from patients with ataxia telangiectasia (7), xeroderma pigmentosum (8), Cockayne s Syndrome (8), and Fanconi s anemia (9) have been tested for polymerase activity. Only the cells from Fanconi s anemia patients exhibited a decreased ability to form poly(ADP)ribose. Apparently, this results from their inherent lower basal levels of the precursor, NAD+ (9). 

W.-S. Cheng, R. E. Tarone, A. D. Andrews, J. S. Whang-Peng, and J. H. Robbins, Ultraviolet light-induced sister chromatid exchanges in xeroderma pigmentosum and in Cockayne s syndrome lymphocyte cell lines. Cancer Res. 38, 1601-1609 (1978). 

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. 

Iyer, N., Reagan, M. S., Wu, K.-J., Canagarajah, B., and Friedberg, E. C. (1996). Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. Biochemistry 35, 2157-2167. 

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