Rules of engagement: centrosome-nuclear connections in a closed mitotic system (original) (raw)
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Centrosomes and mitotic spindle poles: a recent liaison?
Biochemical Society Transactions, 2015
Centrosomes comprise two cylindrical centrioles embedded in the pericentriolar material (PCM). The PCM is an ordered assembly of large scaffolding molecules, providing an interaction platform for proteins involved in signalling, trafficking and most importantly microtubule nucleation and organization. In mitotic cells, centrosomes are located at the spindle poles, sites where spindle microtubules converge. However, certain cell types and organisms lack centrosomes, yet contain focused spindle poles, highlighting that despite their juxtaposition in cells, centrosomes and mitotic spindle poles are distinct physical entities. In the present paper, we discuss the origin of centrosomes and summarize their contribution to mitotic spindle assembly and cell division. We then describe the key molecular players that mediate centrosome attachment to mitotic spindle poles and explore why co-segregation of centrosomes and spindle poles into daughter cells is of potential benefit to organisms.
PLoS Biology, 2010
BICD2 is one of the two mammalian homologues of the Drosophila Bicaudal D, an evolutionarily conserved adaptor between microtubule motors and their cargo that was previously shown to link vesicles and mRNP complexes to the dynein motor. Here, we identified a G2-specific role for BICD2 in the relative positioning of the nucleus and centrosomes in dividing cells. By combining mass spectrometry, biochemical and cell biological approaches, we show that the nuclear pore complex (NPC) component RanBP2 directly binds to BICD2 and recruits it to NPCs specifically in G2 phase of the cell cycle. BICD2, in turn, recruits dynein-dynactin to NPCs and as such is needed to keep centrosomes closely tethered to the nucleus prior to mitotic entry. When dynein function is suppressed by RNA interference-mediated depletion or antibody microinjection, centrosomes and nuclei are actively pushed apart in late G2 and we show that this is due to the action of kinesin-1. Surprisingly, depletion of BICD2 inhibits both dynein and kinesin-1-dependent movements of the nucleus and cytoplasmic NPCs, demonstrating that BICD2 is needed not only for the dynein function at the nuclear pores but also for the antagonistic activity of kinesin-1. Our study demonstrates that the nucleus is subject to opposing activities of dynein and kinesin-1 motors and that BICD2 contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1.
Dictyostelium Sun-1 Connects the Centrosome to Chromatin and Ensures Genome Stability
Traffic, 2008
The nuclear envelope (NE) separates the nuclear compartment from the cytoplasm. It is composed of two membranes: the outer nuclear membrane (ONM) and the inner nuclear membrane (INM). The lumen between the two membranes is the perinuclear space (PNS). The ONM is continuous with the endoplasmic reticulum (ER), whereas the INM harbors a unique set of proteins. INM and ONM proteins can interact within the PNS. Underneath the INM, the nuclear lamina is located, which is formed by intermediate filament (IF) proteins and associated proteins. The lamina forms the nucleoskeleton and associates with the INM, chromatin and nuclear pore complexes. Proteins of the NE have important roles. They are involved in nuclear migration and positioning and are essential for many processes such as mitosis, meiosis, differentiation and cell migration. Furthermore, several of the NE proteins have been associated with inherited diseases (1,2).
The centromere geometry essential for keeping mitosis error free is controlled by spindle forces
Nature, 2007
Accurate segregation of chromosomes, essential for the stability of genome, depends on 'biorientation'-simultaneous attachment of each individual chromosome to both poles of the mitotic spindle 1. On bioriented chromosomes, kinetochores (macromolecular complexes that attach the chromosome to the spindle) reside on the opposite sides of chromosome's centromere 2. In contrast, sister kinetochores shift toward one side of the centromere on 'syntelic' chromosomes that erroneously attach to one spindle pole with both sister kinetochores. Syntelic attachments often arise during spindle assembly and must be corrected to prevent chromosome loss 3. It is assumed that restoration of proper centromere architecture occurs automatically due to elastic properties of the centromere 1, 2. Here we test this assumption by combining laser microsurgery and chemical biology assays. We find that kinetochores of syntelic chromosomes remain juxtaposed upon detachment from spindle microtubules. These findings reveal that correction of syntelic attachments involves an extra step that has previously been overlooked: external forces must be applied to move sister kinetochores to the opposite sides of the centromere. Further, we demonstrate that shape of the centromere is important for spindle assembly, as bipolar spindles do not form is cells lacking centrosomes when multiple chromosomes with juxtaposed kinetochores are present. Thus, proper architecture of the centromere makes an important contribution to achieving high fidelity of chromosome segregation. Kinetochores on bioriented chromosomes are positioned on the opposite sides of the centromere 2. However, during mitotic spindle formation both sister kinetochores sometimes attach to the same spindle pole becoming 'syntelic'. Under this condition, microtubuledependent forces shift sister kinetochores to the same side of the centromere. As syntelic attachment would lead to aneuploidy, this configuration is not stable 4,5. Kinetochore fibres (K-fibres) on syntelic chromosomes depolymerize so that the chromosome moves to the spindle pole where at least one of the two kinetochores detaches from microtubules 6-8. Detached kinetochores can then connect to microtubules from the opposite spindle pole to achieve proper bi-orientation. However, for this mechanism to work properly the shape of the centromere must be restored such that sister kinetochores return to opposite sides of the centromere. It is