We have examined expression from the human cytomegalovirus (CMV) proinoter of a reporter gene encoded in a replication-deficient adenovirus following cellular exposure to heat shock and chemical DNA damaging agents. Expression of the reporter gene was enhanced following prior treatment of cells with cisplatin and N-acetoxy-acetylaminofluorine, but not heat shock. This enhancement was more pronounced and induced by lower chemical concentrations in xeroderma pigmentosum (XP) and Cockayne syndrome fibroblasts that are deficient in the transcription-coupled repair (TCR) pathway of nucleotide excision repair (NER) compared to that in TCR-proficient XP-C and normal strains. This is consistent with an induction of expression from the CMV promoter mediated by persistent (unrepaired) DNA damage in active genes. We show also that expression of the CMV-driven reporter is enhanced following treatment of several human tumour cell lines. This later finding has implications for combined chemotherapy and gene therapy using CMV-driven expression vectors. (C) 2005 Elsevier Inc. All rights reserved.