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Cell cycle Spindle assembly and chromosome separation


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Cell cycle Spindle assembly and chromosome separation

Spindle assembly and chromosome separation

The two critical steps for cell reproduction are to duplicate the contents ofchromosomes and to segregate them into two daughter cells. The linkage between duplicatedchromosomes is established during the S phase (cohesion), persists during their dramaticstructural changes in prometaphase (condensation), and is finally dissolved at themetaphase-anaphase transition (separation) [1].

Microtubes are attached to the kinetochore complex during metaphase-anaphase viaDynein/ Dynactin system. Once microtubes attach, the kinetochore receptor(e.g. Highly expressed in cancer protein ( HEC )) binds to the Mitotic-arrestdeficient 1, yeast, homolog-like 1 ( MAD1 )/ Mitotic-arrest deficient 2, yeast,homolog-like 1 ( MAD2a ) complex with reduced affinity [2]. Inaddition, the cell cycle-regulated serine phosphorylation of HEC by NIMA (never inmitosis gene a)-related kinase 2 ( NEK2A ) is essential for faithful chromosomesegregation [3]. Zeste white 10 homolog ( Zw10 ) and MAD1/MAD2a are simultaneously shed, as Dynein/ Dynactin pulls them offtogether, along the kinetochore microtubes. Removing the MAD1/ MAD2acomplex shuts off the generation of MAD2a/ Cell division cycle 20 homolog (CDC20 ), thus freeing CDC20 for activating the anaphase-promoting complex (APC ) [2].

APC/CDC20 complex is a one of ubiquitin ligases, which plays a key role in thecell cycle. It ubiquitinates proteins, targeting these substrates for degradation by the26S proteasome. APC/CDC20 complex is activated by Cyclin-dependent kinase 1 (CDK1 )/ Cyclin B during metaphase-anaphase [4].

The APC/CDC20 complex -dependent degradation of pituitary tumor-transformingprotein 1 ( Securin ) participate in cleavage of the cohesion complex, therebyallowing sister chromatid separation. The entry into anaphase is marked by the initiationof sister chromatid separation [5]. Moreover, APC/CDC20 complexparticipate in cleavage other members sister chromatid cohesion and chromosomecondensation (e.g. serine/threonine kinase 12 ( Aurora-B ) [6].

The spindle assembly is subjected to the regulatory controls of both the cell-cyclemachinery and the Ras-related nuclear GTP binding protein ( Ran )-signalingpathway. CDK1/Cyclin B kinase phosphorylate the serines located in or near thenuclear localization signal (NLS) of human Regulator of chromosome condensation 1 (RCC1 ), the nucleotide exchange factor for Ran. This phosphorylation is necessaryfor RCC1 to generate Ran-GTP on mitotic chromosomes in mammalian cells,which in turn is required for spindle assembly and chromosome segregation. Moreover,phosphorylation of the NLS of RCC1 is required to prevent the binding of Solublereceptor proteins Karyopherin alpha/beta complex to RCC1, therebyallowing RCC1 to couple Ran-GTP production to chromosome binding [7].

Ran-GTP, in turn, promotes the dissociation of Karyopherin alpha/betacomplex from their cargo proteins and the export of Karyopherins from nucleus.Thus proteins are activated by dissociation of Karyopherins. Some from theseproteins participate in spindle assembly. There are spindle assembly factorsMicrotubule-associated protein homolog Xenopus laevis TPX2 [8] andNuclear mitotic apparatus protein 1 ( NUMA1 ) [9], plus end-directedmicrotubule-based motor Kinesin-like DNA-binding protein ( Kid ) [10].In addition, Ran-GTP participates in activation plus end-directedmicrotubule-based motor Kinesin family member 11 ( KNSL1 ) [11].