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

作者：Wu, Xia; Kabalane, Hadi; Kahli, Malik; Petryk, Nataliya; Laperrousaz, Bastien; Jaszczyszyn, Yan; Drillon, Guenola; Nicolini, Frank-Emmanuel; Perot, Gaelle; Robert, Aude; Fund, Cederic; Chibon, Frederic; Xia, Ruohong; Wiels, Joelle; Argoul, Francois; Maguer-Satta, Veronique; Arneodo, Alain; Audit, Benjamin^*; Hyrien, Olivier^*

来源：Nucleic Acids Research, 2018, 46(19): 10157-10172.

DOI：10.1093/nar/gky797

• CHRONIC MYELOGENOUS LEUKEMIA
• DAMAGE-RESPONSE
• DOMAINS
• STRESS
• LANDSCAPE
• REVEALS
• BARRIER
• MODEL
• GENE
• PART

The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repliseq 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.

• 出版日期2018-11-2
• 单位华东师范大学; 中国地震局