S phase chromatin dynamics safeguard epigenome stability by integrating several processes, including de novo chromatin assembly. Histone chaperone chromatin assembly factor 1, CAF-1, co-ordinates de novo chromatin assembly during DNA replication. Perturbing de novo chromatin assembly in S phase has long-term effects on the epigenome and cell fate; however, the molecular mechanisms are unclear. A study by Dreyer et al. investigated the effects of acute CAF-1 depletion in S phase and uncovered the origins of altered epigenome stability.

The authors found that acute CAF-1 depletion slows DNA replication and prolongs S phase without triggering activation of the ATM or ATR kinases. Further analysis revealed that CAF-1 depletion lowered histone mRNA levels, leading to histone imbalance and delayed chromatin maturation in S phase. The researchers revealed that acute loss of CAF-1 leads to immediate transcriptional effects only during S phase, whereas prolonged CAF-1 loss more broadly affects the cell cycle. Time-lapse imaging showed that impaired de novo chromatin assembly in S phase leads to a G0 arrest.