Resetting a functional G1 nucleus after mitosis

Abstract

The maintenance of the correct cellular information goes beyond the simple transmission of an intact genetic code from one generation to the next. Epigenetic changes, topological cues and correct protein-protein interactions need to be re-established after each cell division to allow the next cell cycle to resume in the correct regulated manner. This process begins with mitotic exit and re-sets all the changes that occurred during mitosis thus restoring a functional G1 nucleus in preparation for the next cell cycle. Mitotic exit is triggered by inactivation of mitotic kinases and the reversal of their phosphorylation activities on many cellular components, from nuclear lamina to transcription factors and chromatin itself. To reverse all these phosphorylations, phosphatases act during mitotic exit in a timely and spatially controlled manner directing the events that lead to a functional G1 nucleus. In this review, we will summarise the recent developments on the control of phosphatases and their known substrates during mitotic exit, and the key steps that control the restoration of chromatin status, nuclear envelope reassembly and nuclear body re-organisation. Although pivotal work has been conducted in this area in yeast, due to differences between the mitotic exit network between yeast and vertebrates, we will mainly concentrate on the vertebrate system.

Keywords: Cell division; Chromatin; Mitotic exit; Nuclear envelope; Phosphatases.

Fig. 1

Phosphatases involved in G1 re-organisation. See text for details

Fig. 2

Phospho-switches in chromatin re-organisation after mitosis. H3K9me3 (1–4) is the docking site for HP1 binding (5–8). In mitosis, H3S10 becomes phosphorylated by Aurora B kinase. This phosphorylation masks the H3K9me3 epitope for antibody recognition in prophase (2) and metaphase (3) but also blocks HP1 from binding (6 and 7). During mitotic exit, the removal of H3S10 phosphorylation by PP1/Repo-Man allows HP1 to target to the chromatin and re-establish the specific chromatin domains (4, 8)

Fig. 3

Molecular gradients in anaphase control the spatial reassembly of nuclear structures after mitosis. 1–2 Dephosphorylation of histone H3 (T3, S10 and S28) starts from the pole-ward side of the segregating chromatids (1,2). The chromatin that is still in the midzone presents high phosphorylation compared to the chromatin at the poles generating a gradient (1”). Aurora B activity in the midzone/midbody coupled to the absence of the H3 counteracting phosphatase activity (Repo-Man/PP1) on the lagging chromatin, maintains a sustained H3 phosphorylation even in late mitosis (2). 3 A molecular gradient is also acting to control the reassembly of the nuclear pore complexes (NPC) during mitotic exit. Importin β and NPC start reassembly around the chromatin from the poleward side