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Nucleic Acids Res. 2018 Nov 2;46(19):10157-10172. doi: 10.1093/nar/gky797.

Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions.

Author information

1
Institut de Biologie de l'École Normale Supérieure (IBENS), Département de Biologie, Ecole Normale Supérieure, CNRS, Inserm, PSL Research University, F-75005 Paris, France.
2
Physics Department, East China Normal University, Shanghai, China.
3
Univ Lyon, ENS de Lyon, Univ Claude Bernard Lyon 1, CNRS, Laboratoire de Physique, F-69342 Lyon, France.
4
CNRS UMR5286, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F- 69008 Lyon, France.
5
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
6
Centre Léon Bérard, F-69008 Lyon, France.
7
INSERM U1218, Institut Bergonié, F-33000 Bordeaux, France.
8
UMR 8126, Université Paris-Sud Paris-Saclay, CNRS, Institut Gustave Roussy, Villejuif, France.
9
École Normale Supérieure, PSL Research University, CNRS, Inserm, IBENS, Plateforme Génomique, 75005 Paris, France.
10
LOMA, Université de Bordeaux, CNRS, UMR 5798, F-33405 Talence, France.

Abstract

The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replication and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types. Importantly, recurrent RFD changes are detected in specific tumour progression pathways. Using a model for establishment and early progression of chronic myeloid leukemia (CML), we identify 1027 replication initiation zones (IZs) that progressively change efficiency during long-term expression of the BCR-ABL1 oncogene, being twice more often downregulated than upregulated. Prolonged expression of BCR-ABL1 results in targeting of new IZs and accentuation of previous efficiency changes. Targeted IZs are predominantly located in GC-poor, late replicating gene deserts and frequently silenced in late CML. Prolonged expression of BCR-ABL1 results in massive deletion of GC-poor, late replicating DNA sequences enriched in origin silencing events. We conclude that BCR-ABL1 expression progressively affects replication and stability of GC-poor, late-replicating regions during CML progression.

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