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Transcription-dependent regulation of replication dynamics modulates genome stability

Abstract : Common fragile sites (CFSs) are loci that are hypersensitive to replication stress and hotspots for chromosomal rearrangements in cancers. CFSs replicate late in S phase, are cell-type specific and nest in large genes. The relative impact of transcription-replication conflicts versus a low density in initiation events on fragility is currently debated. Here we addressed the relationships between transcription, replication, and instability by manipulating the transcription of endogenous large genes in chicken and human cells. We found that inducing low transcription with a weak promoter destabilized large genes, whereas stimulating their transcription with strong promoters alleviated instability. Notably, strong promoters triggered a switch to an earlier replication timing, supporting a model in which high transcription levels give cells more time to complete replication before mitosis. Transcription could therefore contribute to maintaining genome integrity, challenging the dominant view that it is exclusively a threat.
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https://hal.archives-ouvertes.fr/hal-02511509
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Submitted on : Wednesday, March 18, 2020 - 7:18:33 PM
Last modification on : Tuesday, October 19, 2021 - 11:00:28 AM

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Marion Blin, Benoît Le Tallec, Viola Nähse, Mélanie Schmidt, Caroline Brossas, et al.. Transcription-dependent regulation of replication dynamics modulates genome stability. Nature Structural and Molecular Biology, Nature Publishing Group, 2019, 26 (1), pp.58-66. ⟨10.1038/s41594-018-0170-1⟩. ⟨hal-02511509⟩

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