Initiation of DNA replication requires actin dynamics and formin activity

Abstract

<p id="d1274558e416">Nuclear actin regulates transcriptional programmes in a manner dependent on its levels and polymerisation state. This dynamics is determined by the balance of nucleocytoplasmic shuttling, formin‐ and redox‐dependent filament polymerisation. Here, using <i>Xenopus</i> egg extracts and human somatic cells, we show that actin dynamics and formins are essential for <span style="fixed-case">DNA</span> replication. In proliferating cells, formin inhibition abolishes nuclear transport and initiation of <span style="fixed-case">DNA</span> replication, as well as general transcription. In replicating nuclei from transcriptionally silent <i>Xenopus</i> egg extracts, we identified numerous actin regulators, and disruption of actin dynamics abrogates nuclear transport, preventing <span style="fixed-case">NLS</span> (nuclear localisation signal)‐cargo release from Ran <span style="fixed-case">GTP</span>–importin complexes. Nuclear formin activity is further required to promote loading of cyclin‐dependent kinase ( <span style="fixed-case">CDK</span>) and proliferating cell nuclear antigen ( <span style="fixed-case">PCNA</span>) onto chromatin, as well as initiation and elongation of <span style="fixed-case">DNA</span> replication. Therefore, actin dynamics and formins control <span style="fixed-case">DNA</span> replication by multiple direct and indirect mechanisms. </p>