Skip to Main content Skip to Navigation
Journal articles

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

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.
Complete list of metadata

https://hal.inria.fr/hal-02931000
Contributor : Alexy Promonet <>
Submitted on : Wednesday, November 25, 2020 - 3:39:00 PM
Last modification on : Monday, July 5, 2021 - 4:42:04 PM
Long-term archiving on: : Friday, February 26, 2021 - 7:27:16 PM

File

Promonet et al. - Nature Commu...
Files produced by the author(s)

Identifiers

Citation

Alexy Promonet, Ismaël Padioleau, Yaqun Liu, Lionel Sanz, Anna Biernacka, et al.. Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites. Nature Communications, Nature Publishing Group, 2020, 11 (1), ⟨10.1038/s41467-020-17858-2⟩. ⟨hal-02931000⟩

Share

Metrics

Record views

117

Files downloads

226