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Long-term perturbation of de novo chromatin assembly during DNA replication has profound effects on epigenome maintenance and cell fate. The early mechanistic origin of these defects is unknown. Here, we combine acute degradation of chromatin assembly factor 1 (CAF-1), a key player in de novo chromatin assembly, with single-cell genomics, quantitative proteomics, and live microscopy to uncover these initiating mechanisms in human cells. CAF-1 loss immediately slows down DNA replication speed and renders nascent DNA hyper-accessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. In turn, histone variants' usage and their modifications are altered, limiting transcriptional fidelity and delaying chromatin maturation within a single S-phase. This multi-level response induces a p53-dependent cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective de novo chromatin assembly during DNA replication, indicating how at later times the epigenome and cell fate can be altered. [Display omitted] • The histone chaperone CAF-1 sustains DNA replication speed in single cells • CAF-1 loss alters histone repertoire and delays chromatin maturation • H3K9me3 and H3K27me3 regions respond differently to acute CAF-1 depletion • Impaired S-phase chromatin assembly triggers an immediate response and a G0 arrest Dreyer et al. show the broad and rapid impact that acute inhibition of chromatin formation in S-phase has on DNA replication, chromatin stability, and cell-cycle progression. This study sheds light on the molecular mechanisms underlying epigenome inheritance during the cell cycle. [ABSTRACT FROM AUTHOR]

In this issue of Molecular Cell , Hammond et al. (2021) and Piette et al. (2021) identify the essential heat shock co-chaperone DNAJC9 as a new bona fide histone chaperone, linking ATP-dependent molecular chaperones to the histone supply and deposition pathways. [ABSTRACT FROM AUTHOR]