Oct 24, 2018

ATR and mTOR regulate F-actin to alter nuclear architecture and repair replication stress

BioRxiv : the Preprint Server for Biology
Noa LammAnthony Cesare

Abstract

Replication stress describes phenomena that alter DNA replication rates. Multiple architectural challenges within the confined nuclear volume must be navigated during replication to prevent or repair replication stress. Cellular mechanisms potentiating changes in nuclear architecture that facilitate DNA replication remain unclear. Here we show that the ATR, IPMK and mTOR kinases regulate actin polymerisation in human cells to alter nuclear architecture and promote replication fork repair. We demonstrate that replication stress activates mTOR, in an ATR and IPMK-dependent manner, to induce polymerisation of nuclear filamentous actin (F-actin). mTOR and ATR then counteract replication stress-induced nuclear envelope deformation and increase nuclear volume through their regulation of actin dynamics. Additionally, we reveal that FANCD2 labelled replication forks colocalise with actin filaments in late S-phase. mTOR and ATR then regulate the mobility, speed and directionality of stalled replication foci within the three-dimensional nuclear architecture. Importantly, we find nuclear F-actin also acts as a substrate for the directed migration of stalled replication foci to the nuclear periphery. Suppressing mTOR and ATR-dependent acti...Continue Reading

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Mentioned in this Paper

Biochemical Pathway
IPMK gene
Biological Adaptation to Stress
Three-dimensional
Regulation of Biological Process
Actins
Genomic Stability
Virus Replication
FANCD2 gene
FRAP1 protein, human

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