Abstract
DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.
Highlights
DNA replication is a highly complex process that ensures the accurate duplication of the genome, the faithful transmission of genetic material to the cell progeny
We demonstrated that the two cancer cell lines RKO and K562 share strong replication timing” (RT) advances that are poorly enriched in DNA damage signaling histone marks, while being characterized by increases in chromatin accessibility in response to aphidicolin
We demonstrated that the replication timing program is affected in response to low dose of aphidicolin
Summary
DNA replication is a highly complex process that ensures the accurate duplication of the genome, the faithful transmission of genetic material to the cell progeny. Adjacent origins that initiate DNA replication at the same time have been called “replicon clusters” [2], giving rise to chromosomal domains replicating synchronously at given times during the S phase. This coordination of the temporal program of DNA replication, called “replication timing” (RT), allows a complete and faithful duplication of the entire genome before cell division. Additional complex associations have been highlighted such as the link between early-replicating regions and GC nucleotides enrichment, enhanced gene expression, and active epigenetic marks corresponding to open or euchromatin. Late-replicating regions tend to be enriched in AT nucleotides, show low gene content, and have heterochromatin repressive epigenetic marks [12,13]
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