RT Journal Article
SR Electronic
T1 ATR and mTOR regulate F-actin to alter nuclear architecture and repair replication stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 451708
DO 10.1101/451708
A1 Noa Lamm
A1 V. Pragathi Masamsetti
A1 Mark N. Read
A1 Maté Biro
A1 Anthony J. Cesare
YR 2018
UL http://biorxiv.org/content/early/2018/11/19/451708.abstract
AB “Replication stress” describes phenomena that alter DNA replication rates 1–3. 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 actin forces prevents replication fork restart and promotes chromosome segregation errors in primary and cancer cell lines. Together, these data reveal that ATR and mTOR regulate actin dynamics in the replication stress response to alter nuclear architecture and maintain genome stability.