Acute multi-level response to defective de novo chromatin assembly in S-phase

Jan Dreyer; Giulia Ricci; Jeroen van den Berg; Vivek Bhardwaj; Janina Funk; Claire Armstrong; Vincent van Batenburg; Chance Sine; Michael A VanInsberghe; Rinskje B Tjeerdsma; Richard Marsman; Imke K Mandemaker; Simone di Sanzo; Juliette Costantini; Stefano G Manzo; Alva Biran; Claire Burny; Marcel A T M van Vugt; Moritz Völker-Albert; Anja Groth; Sabrina L Spencer; Alexander van Oudenaarden; Francesca Mattiroli

doi:10.1016/j.molcel.2024.10.023

Acute multi-level response to defective de novo chromatin assembly in S-phase

Jan Dreyer, Giulia Ricci, Jeroen van den Berg, Vivek Bhardwaj, Janina Funk, Claire Armstrong, Vincent van Batenburg, Chance Sine, Michael A VanInsberghe, Rinskje B Tjeerdsma, Richard Marsman, Imke K Mandemaker, Simone di Sanzo, Juliette Costantini, Stefano G Manzo, Alva Biran, Claire Burny, Marcel A T M van Vugt, Moritz Völker-Albert, Anja GrothSabrina L Spencer, Alexander van Oudenaarden, Francesca Mattiroli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 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.

Original language	English
Pages (from-to)	4711-4728.e10
Number of pages	29
Journal	Molecular Cell
Volume	84
Issue number	24
Early online date	5-Nov-2024
DOIs	https://doi.org/10.1016/j.molcel.2024.10.023
Publication status	Published - 19-Dec-2024

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Acute multi-level response to defective de novo chromatin assembly in S-phaseFinal publisher's version, 5.44 MBLicence: CC BY-NC-ND

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Dreyer, J., Ricci, G., van den Berg, J., Bhardwaj, V., Funk, J., Armstrong, C., van Batenburg, V., Sine, C., VanInsberghe, M. A., Tjeerdsma, R. B., Marsman, R., Mandemaker, I. K., di Sanzo, S., Costantini, J., Manzo, S. G., Biran, A., Burny, C., van Vugt, M. A. T. M., Völker-Albert, M., ... Mattiroli, F. (2024). Acute multi-level response to defective de novo chromatin assembly in S-phase. Molecular Cell, 84(24), 4711-4728.e10. https://doi.org/10.1016/j.molcel.2024.10.023

@article{2324b4a49ae34cadbf461de6bb972d44,

title = "Acute multi-level response to defective de novo chromatin assembly in S-phase",

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 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.",

author = "Jan Dreyer and Giulia Ricci and {van den Berg}, Jeroen and Vivek Bhardwaj and Janina Funk and Claire Armstrong and {van Batenburg}, Vincent and Chance Sine and VanInsberghe, {Michael A} and Tjeerdsma, {Rinskje B} and Richard Marsman and Mandemaker, {Imke K} and {di Sanzo}, Simone and Juliette Costantini and Manzo, {Stefano G} and Alva Biran and Claire Burny and {van Vugt}, {Marcel A T M} and Moritz V{\"o}lker-Albert and Anja Groth and Spencer, {Sabrina L} and {van Oudenaarden}, Alexander and Francesca Mattiroli",

year = "2024",

month = dec,

day = "19",

doi = "10.1016/j.molcel.2024.10.023",

language = "English",

volume = "84",

pages = "4711--4728.e10",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "24",

}

Dreyer, J, Ricci, G, van den Berg, J, Bhardwaj, V, Funk, J, Armstrong, C, van Batenburg, V, Sine, C, VanInsberghe, MA, Tjeerdsma, RB, Marsman, R, Mandemaker, IK, di Sanzo, S, Costantini, J, Manzo, SG, Biran, A, Burny, C, van Vugt, MATM, Völker-Albert, M, Groth, A, Spencer, SL, van Oudenaarden, A & Mattiroli, F 2024, 'Acute multi-level response to defective de novo chromatin assembly in S-phase', Molecular Cell, vol. 84, no. 24, pp. 4711-4728.e10. https://doi.org/10.1016/j.molcel.2024.10.023

TY - JOUR

T1 - Acute multi-level response to defective de novo chromatin assembly in S-phase

AU - Dreyer, Jan

AU - Ricci, Giulia

AU - van den Berg, Jeroen

AU - Bhardwaj, Vivek

AU - Funk, Janina

AU - Armstrong, Claire

AU - van Batenburg, Vincent

AU - Sine, Chance

AU - VanInsberghe, Michael A

AU - Tjeerdsma, Rinskje B

AU - Marsman, Richard

AU - Mandemaker, Imke K

AU - di Sanzo, Simone

AU - Costantini, Juliette

AU - Manzo, Stefano G

AU - Biran, Alva

AU - Burny, Claire

AU - van Vugt, Marcel A T M

AU - Völker-Albert, Moritz

AU - Groth, Anja

AU - Spencer, Sabrina L

AU - van Oudenaarden, Alexander

AU - Mattiroli, Francesca

PY - 2024/12/19

Y1 - 2024/12/19

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2024.10.023

DO - 10.1016/j.molcel.2024.10.023

M3 - Article

C2 - 39536749

SN - 1097-2765

VL - 84

SP - 4711-4728.e10

JO - Molecular Cell

JF - Molecular Cell

IS - 24

ER -

Acute multi-level response to defective de novo chromatin assembly in S-phase

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