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

Olivier Brison, Sami El-Hilali, Dana Azar, Stéphane Koundrioukoff, Mélanie Schmidt, Viola Nähse, Yan Jaszczyszyn, Anne-Marie Lachages, Bernard Dutrillaux, Claude Thermes, Michelle Debatisse () and Chun-Long Chen ()
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Olivier Brison: CNRS UMR 8200, Gustave Roussy Institute
Sami El-Hilali: Curie Institute, PSL Research University, CNRS UMR 3244
Dana Azar: Curie Institute, PSL Research University, CNRS UMR 3244
Stéphane Koundrioukoff: CNRS UMR 8200, Gustave Roussy Institute
Mélanie Schmidt: CNRS UMR 8200, Gustave Roussy Institute
Viola Nähse: Curie Institute, PSL Research University, CNRS UMR 3244
Yan Jaszczyszyn: Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CNRS, CEA, Paris-Sud University
Anne-Marie Lachages: Curie Institute, PSL Research University, CNRS UMR 3244
Bernard Dutrillaux: CNRS UMR 7205, Museum National d’Histoire Naturelle
Claude Thermes: Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CNRS, CEA, Paris-Sud University
Michelle Debatisse: CNRS UMR 8200, Gustave Roussy Institute
Chun-Long Chen: Curie Institute, PSL Research University, CNRS UMR 3244

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13674-5

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