The effects of camptothecin on RNA polymerase II transcription: roles of DNA topoisomerase I.
Eukaryotic DNA topoisomerase I is active in transcribed chromatin domains to modulate transcription-generated DNA torsional tension. Camptothecin and other agents targeting DNA topoisomerase I are used in the treatment of human solid cancers with significant clinical efficacy. Major progress has been achieved in recent years in the understanding of enzyme structures and basic cellular functions of DNA topoisomerase I. Nevertheless, the precise enzyme functions and mechanisms during transcription-related processes remain unclear. The current understanding of the molecular action of camptothecin emphasizes the drug action against the enzyme and the production of irreversible breaks in the cellular DNA. However, the high drug potency is hardly fully explained by the DNA damage outcome only. In the recent past, several unexpected findings have been reported in relation to the role of eukaryotic topoisomerase I during transcription. In particular, the function of DNA topoisomerase I and the molecular effects of its inhibition on transcription-coupled processes constitute a very active research area. Here, we will briefly review relevant investigations on topoisomerase I involvement in different stages of transcription, discussing both enzyme functions and drug effects on molecular processes.
Capranico
Giovanni
G
Department of Biochemistry, University of Bologna, via Irnerio 48, 40126 Bologna, Italy. giovanni.capranico@unibo.it
Ferri
Francesca
F
Fogli
Maria Vittoria
MV
Russo
Alessandra
A
Lotito
Luca
L
Baranello
Laura
L
D000818:Animals; D002166:Camptothecin / Q000494:pharmacology*; D002843:Chromatin / Q000201:enzymology / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008957:Models, Genetic; D012319:RNA Polymerase II / Q000235:genetics*; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D002843:Chromatin; D012333:RNA, Messenger; D012319:RNA Polymerase II; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin