Transcription-dependent regulation of replication dynamics modulates genome stability

Autor: Marion Blin, Caroline Brossas, Gaël A. Millot, Mélanie Schmidt, Viola Nähse, Marie-Noëlle Prioleau, Michelle Debatisse, Benoît Le Tallec
Přispěvatelé: Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institute for Cancer Research [Oslo], Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The M.D. team is supported by the Agence Nationale de la Recherche (grant ANR-13-BSV6-0008-01/FRA-Dom), the Association pour la Recherche sur le Cancer (grant Subvention Libre Sl220130607073), and the Institut National du Cancer (grants INCa subventions 2013-103 and PLBIO17-194). The M.N.P. team is supported by the Association pour la Recherche sur le Cancer (grant Labellisation PGA120150202272) and the Agence Nationale de la Recherche (grant ANR-15-CE12-0004-01). M.B. was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche and the Ligue contre le cancer., We thank S. Lambert and O. Hyrien for critical reading of the manuscript. The authors would like to acknowledge the Cell and Tissue Imaging Platform – PICT-IBiSA (member of France-Bioimaging) of the Genetics and Developmental Biology Department (UMR3215/U934) of Institut Curie for help with light microscopy, the Flow Cytometry Platform Imagoseine of Institut Jacques Monod, Université Paris Diderot, and the Imaging and Cytometry Platform (PFIC) of Institut Gustave Roussy for assistance with cell sorting., ANR-13-BSV6-0008,FRA-Dom,Chorégraphie des domaines de la chromatine au cours de la différenciation: réorganisation des profils de réplication et des sites fragiles communs(2013), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Faculté de Chirurgie Dentaire (UPD5 Odontologie), Université Paris Descartes - Paris 5 (UPD5), Institut Curie
Rok vydání: 2018
Předmět:
DNA Replication
MESH: Genomic Instability / physiology
Transcription
Genetic
[SDV]Life Sciences [q-bio]
Mitosis
[SDV.CAN]Life Sciences [q-bio]/Cancer
Endogeny
Biology
Genomic Instability
03 medical and health sciences
0302 clinical medicine
Structural Biology
Transcription (biology)
MESH: Transcription
Genetic / genetics
MESH: DNA Replication / genetics
Animals
Humans
MESH: Animals
MESH: Chromosome Fragile Sites / genetics
MESH: Genomic Instability / genetics
Molecular Biology
Gene
030304 developmental biology
Genome stability
0303 health sciences
Replication timing
MESH: Humans
MESH: Mitosis / physiology
Chromosome Fragile Sites
Chromosomal fragile site
Promoter
Cell biology
MESH: Mitosis / genetics
MESH: Chromosome Fragile Sites / physiology
Fragile sites
MESH: DNA Replication / physiology
Transcription
Origin selection
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
030217 neurology & neurosurgery
Zdroj: Nature Structural and Molecular Biology
Nature Structural and Molecular Biology, Nature Publishing Group, 2019, 26 (1), pp.58-66. ⟨10.1038/s41594-018-0170-1⟩
Nature Structural and Molecular Biology, 2019, 26 (1), pp.58-66. ⟨10.1038/s41594-018-0170-1⟩
ISSN: 1545-9985
1545-9993
DOI: 10.1038/s41594-018-0170-1
Popis: International audience; 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.
Databáze: OpenAIRE
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