Deficiencies in mismatch repair have been linked to a common cancer predisposition syndrome in humans, hereditary nonpolyposis colorectal cancer (HNPCC), and a subset of sporadic cancers. Here, several mismatch repair-deficient tumor cell lines and HNPCC-derived lymphoblastoid cell lines were found to be deficient in an additional DNA repair process termed transcription-coupled repair (TCR). The TCR defect was corrected in a mutant cell line whose mismatch repair deficiency had been corrected by chromosome transfer. Thus, the connection between excision repair and mismatch repair previously described in Escherichia coli extends to humans. These results imply that deficiencies in TCR and exposure to carcinogens present in the environment may contribute to the etiology of tumors associated with genetic defects in mismatch repair.

To improve our understanding of the mechanism that couples nucleotide-excision repair to transcription in expressed genes, we have examined the effects of mutations in several different DNA repair genes on the removal of cyclobutane pyrimidine dimers from the individual strands of the induced lactose operon in UV-irradiated Escherichia coli. As expected, we found little repair in either strand of the lactose operon in strains with mutations in established nucleotide excision-repair genes (uvrA, uvrB, uvrC, or uvrD). In contrast, we found that mutations in either of two genes required for DNA-mismatch correction (mutS and mutL) selectively abolish rapid repair in the transcribed strand and render the cells moderately sensitive to UV irradiation. Similar results were found in a strain with a mutation in the mfd gene, the product of which has been previously shown to be required for transcription-coupled repair in vitro. Our results demonstrate an association between mismatch-correction and nucleotide-excision repair and implicate components of DNAmismatch repair in transcription-coupled repair. In addition, they may have important consequences for human disease and may enhance our understanding of the etiology of certain cancers which have been associated with defects in mismatch correction.The selective removal of DNA damage from the transcribed strands of active genes, termed transcription-coupled nucleotide excision repair, may be ubiquitous and has been clearly demonstrated for the removal of UV light-induced cyclobutane pyrimidine dimers (CPDs) (1). In normal human cells (2, 3), Escherichia coli (4), and Saccharomyces cerevisiae (5-8), both strands of active genes are repaired, but CPDs are removed more rapidly from the transcribed strands than from the nontranscribed strands. In rodent cell lines (2), in human xeroderma pigmentosum (XP) group C cell lines (3, 9, 10), and in mutant rad7 and radl6 S. cerevisiae strains (11), CPDs are removed from the transcribed strands of genes, while repair in nontranscribed DNA is inefficient. Conversely, mutations in the E. coli mfd gene (12), the human Cockayne syndrome (CS) group A and B genes (13), and the S. cerevisiae CS-B gene homolog (14) abolish transcription-coupled repair without significantly influencing repair of nontranscribed DNA; repair in transcribed and nontranscribed DNA occurs at similar rates. Clearly, transcription can increase the efficiency of nucleotideexcision repair (NER), transcription-coupled repair can take place even in the absence of overall repair, and there appear to be additional factors that target components of NER to certain lesions present in the transcribed strands of genes.The precise mechanism of transcription-coupled repair in both prokaryotes and eukaryotes is unclear. Several studies indicate that an initial signal is provided by the RNA poly- (12,19) have demonstrated that it is required for transcription-coupled repair in an in vitro system, and the products of the CS genes in human cells are possible candidates for co...