Abstract
To faithfully transmit genetic information, cells must replicate their entire genome before division. This is thought to be ensured by the temporal separation of replication and chromosome segregation. Here we show that in 20–40% of unperturbed yeast cells, DNA synthesis continues during anaphase, late in mitosis. High cyclin-Cdk activity inhibits DNA synthesis in metaphase, and the decrease in cyclin-Cdk activity during mitotic exit allows DNA synthesis to finish at subtelomeric and some difficult-to-replicate regions. DNA synthesis during late mitosis correlates with elevated mutation rates at subtelomeric regions, including copy number variation. Thus, yeast cells temporally overlap DNA synthesis and chromosome segregation during normal growth, possibly allowing cells to maximize population-level growth rate while simultaneously exploring greater genetic space.
Highlights
To faithfully transmit genetic information, cells must replicate their entire genome before division
The ordering of S and M phases is established by increasing levels of cyclin-dependent kinase (Cdk) activity during the cell cycle[2] and is enforced by checkpoints that inhibit chromosome segregation when cells are exposed to severe replication stress[3] or when bulk DNA replication is delayed[4]
Detection of EdU was not affected by differences in cell cycle stage such as chromosome condensation, since EdU incorporated during S phase was detected with similar efficiency in mitosis and interphase (Supplementary Fig. 2)
Summary
To faithfully transmit genetic information, cells must replicate their entire genome before division. The ordering of S and M phases is established by increasing levels of cyclin-dependent kinase (Cdk) activity during the cell cycle[2] and is enforced by checkpoints that inhibit chromosome segregation when cells are exposed to severe replication stress[3] or when bulk DNA replication is delayed[4]. It is unclear how cells could detect unreplicated DNA during unperturbed conditions, and what the detection thresholds of such mechanism may be. Our data suggest that anaphase DNA synthesis of chromosome end regions may contribute to their high mutation rates and rapid evolutionary diversity
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