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- Title
Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription.
- Authors
Tuduri, Sandie; Crabbé, Laure; Conti, Chiara; Tourrière, Hélène; Holtgreve-Grez, Heidi; Jauch, Anna; Pantesco, Véronique; De Vos, John; Thomas, Aubin; Theillet, Charles; Pommier, Yves; Tazi, Jamal; Coquelle, Arnaud; Pasero, Philippe
- Abstract
Topoisomerase I (Top1) is a key enzyme in functioning at the interface between DNA replication, transcription and mRNA maturation. Here, we show that Top1 suppresses genomic instability in mammalian cells by preventing a conflict between transcription and DNA replication. Using DNA combing and ChIP (chromatin immunoprecipitation)-on-chip, we found that Top1-deficient cells accumulate stalled replication forks and chromosome breaks in S phase, and that breaks occur preferentially at gene-rich regions of the genome. Notably, these phenotypes were suppressed by preventing the formation of RNA–DNA hybrids (R-loops) during transcription. Moreover, these defects could be mimicked by depletion of the splicing factor ASF/SF2 (alternative splicing factor/splicing factor 2), which interacts functionally with Top1. Taken together, these data indicate that Top1 prevents replication fork collapse by suppressing the formation of R-loops in an ASF/SF2-dependent manner. We propose that interference between replication and transcription represents a major source of spontaneous replication stress, which could drive genomic instability during the early stages of tumorigenesis.
- Subjects
DNA topoisomerase I; DNA replication; GENETIC transcription; MESSENGER RNA; CHROMOSOMES; GENOMES; CARCINOGENESIS
- Publication
Nature Cell Biology, 2009, Vol 11, Issue 11, p1315
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb1984