Nuclear F-actin counteracts nuclear deformation and promotes fork repair during replication stress

Filamentous actin (F-actin) provides cells with mechanical support and promotes the mobility of intracellular structures. Although F-actin is traditionally considered to be cytoplasmic, here we reveal that nuclear F-actin participates in the replication stress response. Using live and super-resoluti...

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Bibliographic Details
Published in:Nature cell biology Vol. 22; no. 12; pp. 1460 - 1470
Main Authors: Lamm, Noa, Read, Mark N, Nobis, Max, Van Ly, David, Page, Scott G, Masamsetti, V Pragathi, Timpson, Paul, Biro, Maté, Cesare, Anthony J
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.12.2020
Subjects:
Abnormalities
Actin
Actin Cytoskeleton - metabolism
Actins - genetics
Actins - metabolism
Animals
Antineoplastic Agents - pharmacology
Carboplatin - pharmacology
Cell Line
Cell Line, Tumor
Cell Nucleus - genetics
Cell Nucleus - metabolism
Chemotherapy
Chromosomes
DNA Repair - genetics
DNA Replication - genetics
Filaments
Humans
Image resolution
IQGAP1 protein
Mechanistic Target of Rapamycin Complex 1 - genetics
Mechanistic Target of Rapamycin Complex 1 - metabolism
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mobility
Myosin
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
Nuclear deformation
Nucleation
Polymerization
Repair
Replication
TOR protein
Tumors
Xenograft Model Antitumor Assays - methods
Xenografts
Xenotransplantation
ISSN:1465-7392, 1476-4679, 1476-4679
Online Access:Get full text
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Summary:Filamentous actin (F-actin) provides cells with mechanical support and promotes the mobility of intracellular structures. Although F-actin is traditionally considered to be cytoplasmic, here we reveal that nuclear F-actin participates in the replication stress response. Using live and super-resolution imaging, we find that nuclear F-actin is polymerized in response to replication stress through a pathway regulated by ATR-dependent activation of mTORC1, and nucleation through IQGAP1, WASP and ARP2/3. During replication stress, nuclear F-actin increases the nuclear volume and sphericity to counteract nuclear deformation. Furthermore, F-actin and myosin II promote the mobility of stressed-replication foci to the nuclear periphery through increasingly diffusive motion and directed movements along the nuclear actin filaments. These actin functions promote replication stress repair and suppress chromosome and mitotic abnormalities. Moreover, we find that nuclear F-actin is polymerized in vivo in xenograft tumours after treatment with replication-stress-inducing chemotherapeutic agents, indicating that this pathway has a role in human disease.
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ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-020-00605-6