CDK1 and PLK1 co-ordinate the disassembly and re-assembly of the Nuclear Envelope in vertebrate mitosis

Abstract

Micronuclei (MN) arise from chromosomes or fragments that fail to be incorporated into the primary nucleus after cell division. These structures are a major source of genetic instability caused by DNA repair and replication defects coupled to aberrant Nuclear Envelope (NE). These problems ultimately lead to a spectrum of chromosome rearrangements called chromothripsis, a phenomenon that is a hallmark of several cancers. Despite its importance, the molecular mechanism at the origin of this instability is still not understood. Here we show that lagging chromatin, although it can efficiently assemble Lamin A/C, always fails to recruit Nuclear Pore Complexes (NPCs) proteins and that Polo-Like Kinase (PLK1) negatively regulates the NPC assembly. We also provide evidence for the requirement of PLK1 activity for the disassembly of NPCs, but not Lamina (A/C), at mitotic entry. Altogether this study reveals the existence of independent regulatory pathways for Lamin A/C and NPC reorganization during mitosis where Lamin A targeting to the chromatin is controlled by CDK1 activity (a clock-based model) while the NPC loading is also spatially monitored by PLK1.

Protein phosphatases at the nuclear envelope

“…In higher eukaryotes, the nucleus is heavily remodelled during mitosis; this leads to the formation of mitotic chromosomes and the dissociation of the major components of the NE (nuclear envelope), the nuclear pore complexes (NPCs), and the nuclear lamina. This process requires the activation of several kinases including Cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1) [ 1 , 2 ], and the inactivation of protein phosphatases. Once the DNA is separated, the inactivation of CDK1 and PLK1 [ 2 ] coupled to the re-activation of protein phosphatases allows the original nuclear structures to be re-formed [ 3 ].…”

“…This process requires the activation of several kinases including Cyclin-dependent kinase 1 (CDK1) and Polo-like kinase 1 (PLK1) [ 1 , 2 ], and the inactivation of protein phosphatases. Once the DNA is separated, the inactivation of CDK1 and PLK1 [ 2 ] coupled to the re-activation of protein phosphatases allows the original nuclear structures to be re-formed [ 3 ]. Since excellent reviews have dealt with the reformation of the nuclear envelope (NE) in mitosis [ 4 – 6 ], here we summarize only the contribution of phosphatases to the process.…”