Topoisomerase I Suppresses Genomic Instability by Preventing Interference Between Replication and Transcription

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2009 Oct 20

PMID 19838172

Citations 307

Authors

Sandie Tuduri

Laure Crabbe

Chiara Conti

Helene Tourriere

Heidi Holtgreve-Grez

Anna Jauch

Veronique Pantesco

John De Vos

Aubin Thomas

Charles Theillet

Yves Pommier

Jamal Tazi

Arnaud Coquelle

Philippe Pasero

Affiliations

Soon will be listed here.

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.

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