Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity

Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filamen...

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Vydané v:Nature communications Ročník 14; číslo 1; s. 7819 - 15
Hlavní autori: Palumbieri, Maria Dilia, Merigliano, Chiara, González-Acosta, Daniel, Kuster, Danina, Krietsch, Jana, Stoy, Henriette, von Känel, Thomas, Ulferts, Svenja, Welter, Bettina, Frey, Joël, Doerdelmann, Cyril, Sanchi, Andrea, Grosse, Robert, Chiolo, Irene, Lopes, Massimo
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: London Nature Publishing Group UK 28.11.2023
Nature Publishing Group
Nature Portfolio
Predmet:
13
14
14/1
14/19
14/28
631/337/1427/2566
631/337/151/2356
Actin
Actins - genetics
Cell Line, Tumor
Chromatin
Chromosomes
Constraining
Deoxyribonucleic acid
Deregulation
DNA
DNA - genetics
DNA biosynthesis
DNA damage
DNA probes
DNA Replication
Filaments
Genomic instability
Genotoxicity
Humanities and Social Sciences
multidisciplinary
Plastic foam
Plastic properties
Plasticity
Polymerization
Replication
S phase
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
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Shrnutí:Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments. How nuclear architecture assists the replication stress response is still largely unknown. Here the authors show that nuclear actin polymerization rapidly extends upon mild DNA damage. By limiting Primpol activity, this response mediates fork slowing and reversal, protecting chromosome stability.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-43183-5