Acute multi-level response to defective de novo chromatin assembly in S-phase
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.
Authors
- Sabrina L. Spencer (ORCID: https://orcid.org/0000-0002-5798-3007)
- Juliette Costantini
- Claire Burny (ORCID: https://orcid.org/0000-0002-0279-3812)
- Francesca Mattiroli (ORCID: https://orcid.org/0000-0002-1574-7217)
- Vivek Bhardwaj (ORCID: https://orcid.org/0000-0002-5570-9338)
- Stefano Giustino Manzo (ORCID: https://orcid.org/0000-0002-6911-3527)
- Marcel A.T.M. van Vugt (ORCID: https://orcid.org/0000-0002-3202-4678)
- Jan Dreyer
- Alexander van Oudenaarden (ORCID: https://orcid.org/0000-0002-9442-3551)
- Chance Sine (ORCID: https://orcid.org/0000-0002-7184-146X)
- Jeroen van den Berg (ORCID: https://orcid.org/0000-0002-9430-7155)
- Michael VanInsberghe (ORCID: https://orcid.org/0000-0001-8418-4393)
- Imke K. Mandemaker (ORCID: https://orcid.org/0000-0002-5386-6276)
- Vincent van Batenburg (ORCID: https://orcid.org/0000-0003-4203-9571)
- Giulia Ricci
- Anja Groth (ORCID: https://orcid.org/0000-0003-0577-1771)
- Alva Biran (ORCID: https://orcid.org/0000-0002-0276-2004)
- Claire Armstrong (ORCID: https://orcid.org/0000-0003-4387-2450)
- Simone Di Sanzo
- Moritz Völker-Albert (ORCID: https://orcid.org/0009-0003-2946-1169)
- Rinskje B. Tjeerdsma (ORCID: https://orcid.org/0009-0000-1175-8333)
- Richard Marsman
- Janina Funk
Institutions
- University of Copenhagen (DK)
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- University of Colorado Boulder (US)
- Novo Nordisk Foundation (DK)
- Oncode Institute (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
Publication Details
- Journal
- Molecular Cell
- Published
- 2024-11-12
- DOI
- https://doi.org/10.1016/j.molcel.2024.10.023
- Citations
- 14
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 3.27
Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Lundbeckfonden
- Novo Nordisk
- Associazione Italiana per la Ricerca sul Cancro
- Novo Nordisk Fonden
- H. Lundbeck A/S
- National Institutes of Health