Molecular genetics of human diseases with defect in transcription and DNA repair

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To counteract the immediate and cytotoxic response of transcription interference by DNA inzuries, transcription-coupled repair (TCR), a specialized pathway that efficiently removes lesions froom the transcribed strand, has evolved. Genetic defects in TCR form the molecular basis of the severe neuro-developmental disorder Cockayne syndrome (CS), underscoring the biological relevance of TCR. Our aim is to analyze the TCR mechanism and the relevance of its defect to CS symptom. We discovered a novel protein designated XAB2 that interacts with CSA, CSB and RNA polymerase II as well as XPA, and is involved in transcription and TCR. We found That CSA protein is rapidly translocated to the nuclear matrix after UV irradiation. The translocation of CSA (CS group A) required the CSB (CS group B) protein. In UV-irradiated cells, CSA protein co-localized with the hyperphosphorylated form of RNA polymerase II, engaged in transcription elongation. The translocation of CSA was also induced by treatment of the cells with cisplatin or hydrogen peroxide, both of which produce damage that.is subjected to TCR, but not induced by the treatment with dimethyl sulfate, which Produces damage that is not subjected to TCR. The hydrogen peroxide-induced translocation of CSA was also CSB-dependent. These findings establish a link between TCR and the nuclear matrix mediated by CSA. In addition, we report that mice lacking both the XPA (Group A-xeroderma pigmentosum) and CSB genes show apparent ataxia from an early postnatal age and display marked structural abnormalities in cerebellum Reduced neurogenesis and increased apoptotic cell death in the cerebellar external granular layer were also observed. These results indicate that the XPA and CSB gene defects cause neurodysfunctions affecting neuronal cell proliferation and survival, and that XPA and CSB have additive roles in the developing mouse nervous system.