PT  - JOURNAL ARTICLE
AU  - Parisis Nikolaos
AU  - Liliana Krasinska
AU  - Bethany Harker
AU  - Serge Urbach
AU  - Michel Rossignol
AU  - Alain Camasses
AU  - James Dewar
AU  - Nathalie Morin
AU  - Daniel Fisher
TI  - Initiation of DNA replication requires actin dynamics and formin activity
AID  - 10.1101/102806
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 102806
4099  - http://biorxiv.org/content/early/2017/01/28/102806.short
4100  - http://biorxiv.org/content/early/2017/01/28/102806.full
AB  - Nuclear actin influences transcription in a manner dependent on its dynamics of polymerisation and nucleocytoplasmic translocation. Using human somatic cells and transcriptionally-silent Xenopus egg extracts, we show that actin dynamics is also required for DNA replication. We identify many actin regulators in replicating nuclei from Xenopus egg extracts, and show that in human cells, nuclear actin filaments form in early G1 and disassemble prior to S-phase. In either system, treatments that stabilise nuclear actin filaments abrogate nuclear transport and initiation of DNA replication. Mechanistically, actin directly binds RanGTP-importin complexes and disruption of its dynamics hinders cargo release. This prevents both nuclear pore complex (NPC) formation and active nuclear transport, which we show is required throughout DNA replication. Nuclear formin activity is required for two further steps: loading of cyclin-dependent kinase (CDK) and proliferating cell nuclear antigen (PCNA) onto chromatin and initiation of DNA replication. Thus, actin dynamics and formins are involved in several nuclear processes essential for cell proliferation.