Acute multi-level response to defective de novo chromatin assembly in S-phase.
Jan DreyerGiulia RicciJeroen van den BergVivek BhardwajJanina FunkClaire ArmstrongVincent van BatenburgChance SineMichael A VanInsbergheRichard MarsmanImke K MandemakerSimone di SanzoJuliette CostantiniStefano G ManzoAlva BiranClaire BurnyMoritz Völker-AlbertAnja GrothSabrina L SpencerAlexander van OudenaardenFrancesca MattiroliPublished in: bioRxiv : the preprint server for biology (2024)
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 hyperaccessible. A rapid cellular response, distinct from canonical DNA damage signaling, is triggered and lowers histone mRNAs. As a result, 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 cell-cycle arrest after mitosis. Our work reveals the immediate consequences of defective de novo chromatin assembly during DNA replication, explaining how at later times the epigenome and cell fate can be altered.
Keyphrases
- dna damage
- gene expression
- cell fate
- dna methylation
- transcription factor
- genome wide
- single cell
- dna repair
- oxidative stress
- liver failure
- cell cycle arrest
- single molecule
- high resolution
- copy number
- mass spectrometry
- high throughput
- drug induced
- respiratory failure
- cell proliferation
- optical coherence tomography
- quantum dots
- sensitive detection
- label free
- acute respiratory distress syndrome
- high speed
- circulating tumor cells