DESCRIPTION: The broad objective of this proposal is to elucidate the molecular mechanisms involved in transcription-coupled repair (TCR) in mammalian cells of DNA lesions induced by ionizing radiation and other agents that produce oxidative damage. Previous studies have shown that TCR is a discrete pathway for removal of lesions that block transcription and that it directs base excision repair (BER) to oxidative lesions. TCR requires the Cockayne syndrome group B (CSB) protein, the xeroderma pigmentosum group G (XPG) protein and also the XPB and XPD proteins. Examination of different alleles in these genes has revealed that their functions in TCR are separable from their functions in nucleotide excision repair (NER) and that defects in the former are linked to the clinical appearance of the developmental disorder Cockayne syndrome. The overall hypothesis to be tested here are that (a) XPG recruits appropriate repair proteins to lesions that are blocking transcription, and that (b) the intact TCR machinery removes the stalled RNA polymerase (RNAP) to allow repair to occur. Understanding of protein-protein and protein-DNA interactions of XPG will be important for dissecting the multiple functions of this protein and the molecular machine that couples lesion removal to transcription. These studies will advance our understanding of how cells cope with cellular oxidative damage to DNA.