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eSymposia | Genomic Stability and DNA Repair


Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

Description

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells Background DNA replication is very well orchestrated in mammalian cells thanks to a tight regulation of the temporal order of replication origin activation, commonly called replication timing. The replication timing of a given replication domain is very robust and well conserved in each cell type. Upon low replication stress, the slowing down of replication forks slow down induces delayed replication of some fragile regions, leading to DNA damage and genetic instability. Except for these fragile regions, the direct impact of low replication stress on the replication timing of the whole genome in different cellular backgrounds has not been explored in detail. Results Thanks to whole genome analysis of DNA replication timing in 6 human cell lines, we demonstrate that low replication stress induced by aphidicolin has a stronger impact on replication timing of cancer cells than normal cells and strikingly, we unveiled specific replication domains undergoing a large switch from late to early replication. Thanks to ATAC-seq experiments, we further demonstrated that aphidicolin induces a global opening of the chromatin that correlate with replication timing advances. Finally, our data indicate that replication timing advances can be inherited by the next cellular generation that is not anymore treated by aphidicolin leading to the up regulation of the genes they contain. Conclusion This study reveals the existence of specific heterochromatin domains in cancer cells that are prone to advance their replication timing in response to replication stress. This adaptive response might impact cell fate, increasing variability and resilience of cancer cells to a changing and hostile environment.

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