Cockayne syndrome

Theron T, Fousteri MI, Volker M, Harries LW, Botta E, Stefanini M, Fujimoto M, Andressoo JO, Mitchell J, Jaspers NG, McDaniel LD, Mullenders LH, Lehmann AR (2005) Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne syndrome. Mol Cell Biol 25(18) 8368-8378 Thiriet C, Hayes JJ (2005) Chromatin in need of a fix phosphorylation of H2AX connects chromatin to DNA repair. Mol Cell 18(6) 617-622... 

CSB/ERCC6 CSB Human Associates with a subset of Pol II complexes Mutation causes Cockayne syndrome, a defect in transcription coupled nucleotide excision repair [321,322]. Human Rad26p homolog... 

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. 

Kim, N., Kage, K., Matsuda, F., Lefranc, M.-P., Storb, U. (1997). B lymphocytes of xeroderma pigmentosum or Cockayne syndrome patients with inherited defects in nucleotide excision repair are fully capable of somatic hypermutation of immunoglobulin genes. J. Exp. Med. 186,413-419. 

Henning KA, Li L, Iyer N et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 1995 82(4) 555-564. 

Cockayne syndrome (CS) patients with mutation in the CSA or CSB gene are completely deficient in TCR-NER, but proficient in GGR. This rare hereditary disease is characterized by postnatal growth failure and early onset of severe neurobiological abnormalities, but no cancers [75]. This may be explained by the fact that the TCR defect causes CS cells to be particularly sensitive to lesion-induced apoptosis, thereby protecting against tumor genesis [17]. This syndrome emphasizes the importance of specific repair of actively transcribed DNA. 

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... 

Tuo, J., Jaruga, P., Rodriguez, H., Dizdaroglu, M., and Bohr, V.A. (2002) The Cockayne syndrome group B gene product is involved in cellular repair of 8-hydroxyadenine in DNA. J. Biol. 

Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine from oxidative sttess. FASEBJ., 17, 668-674. 

By contrast, deficiencies in GG-NER (see Section 11.3) lead to the inherited disorder xeroderma pigmentosum (XP), which can be viewed as the prototypical DNA repair disorder [7-9]. XP patients are unable to repair UV lesions, and as a consequence suffer from an extreme sensitivity to UV light and an over 1000-fold increased incidence of skin cancer. Severely affected XP patients additionally suffer from neurological abnormalities. The phenotypes of two additional symptoms associated with NER genes, Cockayne syndrome (CS) and trichothiodystro-phy (TTD), are more complex as they are due to defects in transcription as well as defects in DNA repair [10]. 

Bootsma, D Kraemer, K.H., Cleaver, J.E., and Hoeijmakers, J.H.J. (1998) Nucleotide excision repair syndromes xeroderma pigmentosum, cockayne syndrome, and trichothiodystrophy, in The Genetic Basis of Cancer (eds B. Vogelstein and K.W. Kinzler), McGraw-Hill, New York, pp. 245-274. 

Lehmann, A.R. (2003) DNA repair -deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie, 85, 1101-1111. 

Kraemer, K.H., Patronas, N.J., Schiffmann, R., Brooks, B.P., Tamura, D., and DiGiovanna, J.J. (2007) Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome a complex genotype-phenotype relationship. Neuroscience, 145,1388-1396. 

Venema, J., Mullenders, L, Natarajan, A., Zeeland, A., and Mayne, L. (1990) The genetic defect in Cockayne syndrome is assodated with a defed in repair of UV-induced DNA damage in transcriptionally active DNA. Proc. Natl. Acad. Sci. USA, 87, 4707-4711. 

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