Nucleotide excision repair "a legacy of creativity"

The first half of the 20th century has seen an enormous growth in our knowl edge of DNA repair, in no small part due to the work of Dirk Bootsma, Phili p Hanawalt and Bryn Bridges; those honored by this issue. For the new mille nnium, we have asked three general questions: (A) Do we know all possible s trategies of nucleotide excision repair (NER) in all organisms? (B) How is NER integrated and regulated in cells and tissues? (C) Does DNA replication represent a new frontier in the roles of DNA repair? We make some suggesti ons for the kinds of answers the next generation may provide. The kingdom o f archea represents an untapped field for investigation of DNA repair in or ganisms with extreme lifestyles. NER appears to involve a similar strategy to the other kingdoms of prokaryotes and eukaryotes, but subtle differences suggest that individual components of the system may differ. NER appears t o be regulated by several major factors, especially p53 and Rb which intera ct with transcription coupled repair and global genomic repair, respectivel y. Examples can be found of major regulatory changes in repair in testicula r tissue and melanoma cells. Our understanding of replication of damaged DN A has undergone a revolution in recent years, with the discovery of multipl e low-fidelity DNA polymerases that facilitate replicative bypass. A second ary mechanism of replication in the absence of NER or of one or more of the se polymerases involves sister chromatid exchange and recombination (hMre11 /hRad50/Nbs1). The relative importance of bypass and recombination is deter mined by the action of p53. We hypothesise that these polymerases may be in volved in resolution of complex DNA structures during completion of replica tion and sister chromatid resolution. With these fascinating problems to in vestigate, the field of DNA repair will surely not disappoint the next gene ration. (C) 2001 Elsevier Science B.V. All rights reserved.