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

Autor: Brison O; CNRS UMR 8200, Gustave Roussy Institute, F-94805, Villejuif, France.; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France., El-Hilali S; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France.; Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CNRS, CEA, Paris-Sud University, F-91198, Gif-sur-Yvette, France., Azar D; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France.; Laboratoire Biodiversite et Genomique Fonctionnelle, Faculte des Sciences, Universite Saint-Joseph, 1107 2050, Beirut, Lebanon., Koundrioukoff S; CNRS UMR 8200, Gustave Roussy Institute, F-94805, Villejuif, France.; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France., Schmidt M; CNRS UMR 8200, Gustave Roussy Institute, F-94805, Villejuif, France., Nähse V; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Jaszczyszyn Y; Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CNRS, CEA, Paris-Sud University, F-91198, Gif-sur-Yvette, France.; Paris-Saclay University, F-91198, Gif-sur-Yvette, France., Lachages AM; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France.; Sorbonne University, F-75005, Paris, France.; UTCBS, CNRS UMR 8258/ INSERM U 1267, Sorbonne-Paris-Cité University, F-75006, Paris, France., Dutrillaux B; CNRS UMR 7205, Museum National d'Histoire Naturelle, F-75005, Paris, France., Thermes C; Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CNRS, CEA, Paris-Sud University, F-91198, Gif-sur-Yvette, France.; Paris-Saclay University, F-91198, Gif-sur-Yvette, France., Debatisse M; CNRS UMR 8200, Gustave Roussy Institute, F-94805, Villejuif, France. michelle.debatisse@gustaveroussy.fr.; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France. michelle.debatisse@gustaveroussy.fr.; Sorbonne University, F-75005, Paris, France. michelle.debatisse@gustaveroussy.fr., Chen CL; Curie Institute, PSL Research University, CNRS UMR 3244, F-75005, Paris, France. chunlong.chen@curie.fr.; Sorbonne University, F-75005, Paris, France. chunlong.chen@curie.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Dec 13; Vol. 10 (1), pp. 5693. Date of Electronic Publication: 2019 Dec 13.
DOI: 10.1038/s41467-019-13674-5
Abstrakt: 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.
Databáze: MEDLINE
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