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

X.Wu, H.Kabalane, M.Kahli, [...] A.Arneodo, B.Audit, O.Hyrien

Xia Wu, Hadi Kabalane, Malik Kahli, Nataliya Petryk, Bastien Laperrousaz, Yan Jaszczyszyn, Guenola Drillon, Frank-Emmanuel Nicolini, Gaëlle Perot, Aude Robert, Cédric Fund, Frédéric Chibon, Ruohong Xia, Joëlle Wiels, Françoise Argoul, Véronique Maguer-Satta, Alain Arneodo, Benjamin Audit & Olivier Hyrien.

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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Nucleic Acids Res. 2018 Sep 5. doi:10.1093/nar/gky797