Nuclear tension controls mitotic entry by regulating cyclin B1 nuclear translocation

Abstract

As cells prepare to divide, they must ensure that enough space is available to assemble the mitotic machinery without perturbing tissue homeostasis. To do so, cells undergo a series of biochemical reactions regulated by cyclin B1-CDK1 that trigger cytoskeletal reorganization and ensure the coordination of cytoplasmic and nuclear events. Along with the biochemical events that control mitotic entry, mechanical forces have recently emerged as important players in cell-cycle regulation. However, the exact link between mechanical forces and the biochemical pathways that control mitotic progression remains unknown. Here, we identify a tension-dependent signal on the nucleus that sets the time for nuclear envelope permeabilization (NEP) and mitotic entry. This signal relies on actomyosin contractility, which unfolds the nucleus during the G2-M transition, activating the stretch-sensitive cPLA2 on the nuclear envelope and regulating the nuclear translocation of cyclin B1. Our data demonstrate how nuclear tension during the G2-M transition contributes to timely and efficient mitotic spindle assembly and prevents chromosomal instability.

The LINC complex ensures accurate centrosome positioning during prophase

“…S3I; ****p<0.0001) (Appelbaum et al 1990). It has been previously shown that LBR overexpression causes perinuclear ER expansion and the overproduction of nuclear membranes (Ma et al 2007), leading to NE folding and altered nuclear structure (Dantas et al 2022), similar to what we observed in U2-OS and MDA-MB-468 cells. However, interfering with nuclear structure by overexpressing LBR in RPE-1 cells (Fig.…”

“…To do so, we overexpressed an mCherry-tagged version of lamin B receptor (LBR), an integral protein of the inner nuclear membrane (INM) that associates with the nuclear lamina 43 . It has been previously shown that LBR overexpression causes perinuclear ER expansion and the overproduction of nuclear membranes 44 , leading to NE folding and altered nuclear structure 45 , similar to what we observed in U2-OS and MDA-MB-468 cells. However, interfering with nuclear structure by overexpressing LBR in RPE-1 cells (Fig.…”

Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

“…Our dissipative particle dynamics (DPD) model has qualitatively recapitulated the experimental results from living cells that mechanomemory persists in the chromatin, and nucleoplasm diffusivity for tens of minutes after stress cessation and this memory is regulated by the NPCs. Recent reports show that the size of and the transport via the NPCs that is tethered to the cytoskeleton is regulated by the tension in the nuclear envelope ( 21 , 27 ), and transport of RNA via NPCs is unidirectional ( 28 ). Our current finding that the mechanomemory of chromatin diffusivity and nucleoplasm protein diffusivity extends the current understanding of the role of the NPCs and highlights the importance of the molecular exchange between the nucleus and the cytoplasm in regulating external force-induced nuclear activities and functions.…”

“…FRET was obtained to assess the heterochromatin condensation state between HP1α-GFP/mCherry and MBD1-EGFP/mCherry ( 40 ). The FRET efficiency (η) was quantified using the following equation ( 27 ): …”

Mitosis sets nuclear homeostasis of cancer cells under confinement

“…Several groups identified an alteration of cell mitosis under such confined situations (11,12), with modified cell cycle progression and division (13), the presence of multi-daughter events, daughter cells of unequal size, and induction of cell death (14). Moreover, such flattening was shown to promote the G1-S transition (15), as well as the G2-M transition (16), thus fostering cell cycle progression. Under such confined conditions, the nucleus was highlighted as a mechanosensor (17)(18)(19), triggering a mechanism of nuclear repair (20) and rescue of DNA damage (21).…”