Controlling the efficiency of excision repair

The early studies are recounted, that led to the discovery of the ubiquitou s process of DNA excision repair, followed by a review of the pathways of t ranscription-coupled repair (TCR) and global genomic nucleotide excision re pair (GGR). Repair replication of damaged DNA in UV-irradiated bacteria was discovered through the use of 5-bromouracil to density-label newly synthes ized DNA. This assay was then used in human cells to validate the phenomeno n of unscheduled DNA synthesis as a measure of excision repair and to eluci date the first example of a DNA repair disorder, xeroderma pigmentosum. Fea tures of the TCR pathway (that is defective in Cockayne syndrome (CS)) incl ude the possibility of "gratuitous TCR" at transcription pause sites in und amaged DNA. The GGR pathway is shown to be controlled through the SOS stres s response in E. coli and through the activated product of the p53 tumor su ppressor gene in human cells. These regulatory systems particularly affect the efficiency of repair of the predominant UV-induced photoproduct, the cy clobutane pyrimidine dimer, as well as that of chemical carcinogen adducts, such as benzo(a)pyrene diol-epoxide. Rodent cells (typically lacking the p 53-controlled GGR pathway) and tumor virus infected human cells tin which p 53 function is abrogated) are unable to carry out efficient GGR of some les ions. Therefore, caution should be exercised in the interpretation of resul ts from such systems for risk assessment in genetic toxicology. Many proble ms in excision repair remain to be solved, including the mechanism of scann ing the DNA for lesions and the subcellular localization of the repair fact ories. Also there are persisting questions regarding the multiple options o f repair, recombination, and translesion synthesis when replication forks e ncounter lesions in the template DNA. That is where the field of DNA excisi on repair began four decades ago with studies on the recovery of DNA synthe sis in UV-irradiated bacteria. (C) 2001 Elsevier Science B.V. All rights re served.