DNA topoisomerase i as a transcription protein and a lethal cellular toxin.
DNA topoisomerase I constitutes a significant relaxing activity in nuclei of eukaryotic cells. The enzyme acts during several DNA transactions involving the generation of torsional stress in the DNA template. Moreover, antitumor agents targeting DNA topoisomerase I are used in the treatment of human cancers with significant clinical outcome. Major progress has been attained in recent years in the understanding of the basic cellular functions of DNA topoisomerase I. In particular, the consequences of topoisomerase I activity during transcription have been extensively investigated and constitute still a very active research area. Understanding of topoisomerase I inhibitors emphasizes drug activity against the enzyme, however the high drug potency cannot be explained by the DNA damage outcome only. Even though the understanding of enzyme structure has progressed in last years, however more insights into the activity of topoisomerase I poisons have not been achieved yet. Here, we will review landmark investigations on topoisomerase I involvement in different stages of the transcription process, addressing both enzyme functions as well as drug effects on molecular processes. Moreover, we will discuss recent findings on the targeting of topoisomerase I to pre-selected sites in transcribed chromatin by fusion to a sequence-specific DNA-binding protein domain.
Lotito
Luca
L
Department of Biochemistry, University of Bologna, Bologna, Italy.
Ferri
Francesca
F
Russo
Alessandra
A
Capranico
Giovanni
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005057:Eukaryotic Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D002843:Chromatin; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; D004264:DNA Topoisomerases, Type I