Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Nature Communications Année : 2019

Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide

Résumé

Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known to drive chromosome rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide replication timing analyses here show that stress-induced delayed/under-replication is the hallmark of CFSs. Extensive genome-wide analyses of nascent transcripts, replication origin positioning and fork directionality reveal that 80% of CFSs nest in large transcribed domains poor in initiation events, replicated by long-travelling forks. Forks that travel long in late S phase explains CFS replication features , whereas formation of sequence-dependent fork barriers or head-on transcription-replication conflicts do not. We further show that transcription inhibition during S phase, which suppresses transcription-replication encounters and prevents origin resetting, could not rescue CFS stability. Altogether, our results show that transcription-dependent suppression of initiation events delays replication of large gene bodies, committing them to instability.
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Dates et versions

hal-02430920 , version 1 (07-01-2020)

Identifiants

Citer

Olivier Brison, Sami El-Hilali, Dana Azar, Stéphane Koundrioukoff, Mélanie Schmidt, et al.. Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide. Nature Communications, 2019, 10, pp.5693. ⟨10.1038/s41467-019-13674-5⟩. ⟨hal-02430920⟩
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