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Acute multi-level response to defective de novo chromatin assembly in S-phase.
Dreyer, Jan; Ricci, Giulia; van den Berg, Jeroen; Bhardwaj, Vivek; Funk, Janina; Armstrong, Claire; van Batenburg, Vincent; Sine, Chance; VanInsberghe, Michael A; Marsman, Richard; Mandemaker, Imke K; di Sanzo, Simone; Costantini, Juliette; Manzo, Stefano G; Biran, Alva; Burny, Claire; Völker-Albert, Moritz; Groth, Anja; Spencer, Sabrina L; van Oudenaarden, Alexander; Mattiroli, Francesca.
Afiliación
  • Dreyer J; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Ricci G; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • van den Berg J; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Bhardwaj V; Oncode Institute, The Netherlands.
  • Funk J; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Armstrong C; Oncode Institute, The Netherlands.
  • van Batenburg V; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Sine C; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA.
  • VanInsberghe MA; BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
  • Marsman R; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Mandemaker IK; Oncode Institute, The Netherlands.
  • di Sanzo S; Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA.
  • Costantini J; BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA.
  • Manzo SG; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Biran A; Oncode Institute, The Netherlands.
  • Burny C; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Völker-Albert M; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • Groth A; MOLEQLAR Analytics GmbH, Rosenheimer Street 141 h, 81671 Munich, Germany.
  • Spencer SL; Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
  • van Oudenaarden A; Oncode Institute, The Netherlands.
  • Mattiroli F; Division of Gene Regulation, Netherlands Cancer Institute, The Netherlands.
bioRxiv ; 2024 Mar 27.
Article en En | MEDLINE | ID: mdl-38585916
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos