Transcription-coupled repair and its deficiency

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Nucleotide excision repair (NER) removes a wide variety of lesions from the genome and is defective in the genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS). Complementation studies revealed that 7 genes are involved in XP (XPA-XPG) and 2 in CS (CSA, CSB). There are two subpathways in NER : transcription-coupled (TC-)NER accomplishing efficient removal of lesions blocking transcription and the slower global genome (GG-)NER.(1) We recently discovered a novel 855-amino acid protein, XAB2 (XPA-binding protein 2), containing 18 tetratricopeptide repeats, by virtue of its ability to interact with XPA in yeast two hybrid system. Immunoprecipitation analysis demonstrated that XAB2 is associated with the TC-NER-specific proteins CSA, CSB and RNA polymerase II in vivo. Antibodies against XAB2 inhibited both TCR and transcription when microinjected into living fibroblasts. These results indicate that XAB2 is a novel component involved in TC-NER and transcription. (2) XPA- o … More r CSB-deflcient mice were generated. A very important discovery was made when XPA-deficient micethat develop normally was crossed with the CSB-deflcient mice to generate double knockout mice. The double knockout mice appear to exhibit very severe synergistic developmental impairment resulting in extremely early ceasing of developmenta and death 4-6 weeks after birth. These results indicate that CSB and XPA belong to the different epistatic groups and that DNA damage and transcriptional competance contribute to the process of aging. (3) To find out whether NER contributes to preferential removal of 06-EtGua from active genes (asobserved in mammary cells of the rat and thymus cells of the mouse) repair kinetics for this a dduct have been measured in DNA from different tissues of EtNU-exposed XPA +/- and XPA -/- mice. For tissue-specific global repair of 06-EtGua no significant differences were observed between XPA knock out and heterozygote mice. However, this lesion was removed 3-4 times faster from active genes than from total genomic DNA in liver and brain cells of XPA +/- animals. This preferential repair was not observed in the XPA knock out mice. These results indicate that 06-EtGua in the active gene is repaired by NER. Less