Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites

Alexy Promonet, Ismaël Padioleau, Yaqun Liu, Lionel Sanz, Anna Biernacka, Anne-Lyne Schmitz, Magdalena Skrzypczak, Amélie Sarrazin, Clément Mettling, Maga Rowicka, Krzysztof Ginalski, Frédéric Chedin, Chun-Long Chen (), Yea-Lih Lin () and Philippe Pasero ()
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Alexy Promonet: Equipe labélisée Ligue contre le Cancer
Ismaël Padioleau: Equipe labélisée Ligue contre le Cancer
Yaqun Liu: Sorbonne Université
Lionel Sanz: University of California
Anna Biernacka: University of Warsaw
Anne-Lyne Schmitz: Equipe labélisée Ligue contre le Cancer
Magdalena Skrzypczak: University of Warsaw
Amélie Sarrazin: CNRS et Université de Montpellier
Clément Mettling: CNRS et Université de Montpellier
Maga Rowicka: University of Texas Medical Branch at Galveston
Krzysztof Ginalski: University of Warsaw
Frédéric Chedin: University of California
Chun-Long Chen: Sorbonne Université
Yea-Lih Lin: Equipe labélisée Ligue contre le Cancer
Philippe Pasero: Equipe labélisée Ligue contre le Cancer

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract R-loops have both positive and negative impacts on chromosome functions. To identify toxic R-loops in the human genome, here, we map RNA:DNA hybrids, replication stress markers and DNA double-strand breaks (DSBs) in cells depleted for Topoisomerase I (Top1), an enzyme that relaxes DNA supercoiling and prevents R-loop formation. RNA:DNA hybrids are found at both promoters (TSS) and terminators (TTS) of highly expressed genes. In contrast, the phosphorylation of RPA by ATR is only detected at TTS, which are preferentially replicated in a head-on orientation relative to the direction of transcription. In Top1-depleted cells, DSBs also accumulate at TTS, leading to persistent checkpoint activation, spreading of γ-H2AX on chromatin and global replication fork slowdown. These data indicate that fork pausing at the TTS of highly expressed genes containing R-loops prevents head-on conflicts between replication and transcription and maintains genome integrity in a Top1-dependent manner.

Date: 2020
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DOI: 10.1038/s41467-020-17858-2

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