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Nat Cell Biol. 2009 Nov;11(11):1315-24. doi: 10.1038/ncb1984. Epub 2009 Oct 18.

Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription.

Author information

1
Institute of Human Genetics CNRS UPR1142, F-34396 Montpellier, France.

Erratum in

  • Nat Cell Biol. 2010 Nov;12(11):1122.

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.

PMID:
19838172
PMCID:
PMC2912930
DOI:
10.1038/ncb1984
[Indexed for MEDLINE]
Free PMC Article

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