title: Genome-wide transcriptional effects of the anti-cancer agent camptothecin.
abstract: The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a "cleavable complex". To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5'-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B), which are defective in transcription-coupled repair (TCR), showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons.
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center and Translational Oncology Program, University of Michigan, Ann Arbor, Michigan, United States of America ; Bioinformatics Program and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Artur
authors.initials: A
authors.lastname: Veloso
authors.forename: Benjamin
authors.initials: B
authors.lastname: Biewen
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Paulsen
authors.forename: Nathan
authors.initials: N
authors.lastname: Berg
authors.forename: Leonardo
authors.initials: L
authors.lastname: Carmo de Andrade Lima
authors.forename: Jayendra
authors.initials: J
authors.lastname: Prasad
authors.forename: Karan
authors.initials: K
authors.lastname: Bedi
authors.forename: Brian
authors.initials: B
authors.lastname: Magnuson
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wilson
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001483:Base Sequence; D002166:Camptothecin / Q000494:pharmacology*; D004265:DNA Helicases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015723:Gene Library; D016678:Genome / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D000075223:Poly-ADP-Ribose Binding Proteins; D017422:Sequence Analysis, DNA; D061805:Transcription Elongation, Genetic / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000075223:Poly-ADP-Ribose Binding Proteins; D004265:DNA Helicases; C078673:ERCC6 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D045643:DNA Repair Enzymes; D002166:Camptothecin