Transcription-dependent regulation of replication dynamics modulates genome stability

被引:61
作者
Blin, Marion [1 ,2 ,3 ,7 ]
Le Tallec, Benoit [1 ,2 ,3 ,8 ]
Nahse, Viola [1 ,2 ,3 ,9 ,10 ]
Schmidt, Melanie [4 ]
Brossas, Caroline [5 ]
Millot, Gael A. [6 ]
Prioleau, Marie-Noelle [5 ]
Debatisse, Michelle [1 ,2 ,3 ,11 ]
机构
[1] Inst Curie, Ctr Rech, Paris, France
[2] Univ Paris 06, Sorbonne Univ, Paris, France
[3] CNRS, UMR 3244, Paris, France
[4] Inst Gustave Roussy, CNRS, UMR 8200, Villejuif, France
[5] Univ Paris Diderot, Inst Jacques Monod, CNRS, UMR 7592, Paris, France
[6] Inst Pasteur, Bioinformat & Biostat Hub, C3BI, CNRS,USR IP 3756, Paris, France
[7] Aix Marseille Univ, CNRS, Inst Paoli Calmettes, INSERM,CRCM, Marseille, France
[8] PSL Univ Paris, CNRS, IBENS, Ecole Normale Super,INSERM, Paris, France
[9] Oslo Univ Hosp, Inst Canc Res, Dept Mol Cell Biol, Montebello, Oslo, Norway
[10] Univ Oslo, Inst Clin Med, Ctr Canc Cell Reprogramming, Fac Med, Oslo, Norway
[11] Inst Gustave Roussy, CNRS, UMR 8200, Villejuif, France
关键词
COMMON FRAGILE SITES; DNA-REPLICATION; GENE-EXPRESSION; STRESS; ORIGIN; INITIATION; TRACTS; SPECIFICATION; INSTABILITY; MECHANISM;
D O I
10.1038/s41594-018-0170-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:58 / +
页数:12
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