In What Cell Stage Are You Unable to See Individual Chromosomes

Chromosome Segregation

Human being Genetics and Patterns of Inheritance

Robert Resnik Doc , in Creasy and Resnik'south Maternal-Fetal Medicine: Principles and Practice , 2019

Nondisjunction

Nondisjunction is an mistake in meiosis that results from failure of either tetrad separation in anaphase I or sis chromatid separation in anaphase 2. Aneuploidy, proceeds or loss of at least 1 chromosome, is the result. Aneuploidy of chromosome 21 (i.e., Down's syndrome) is associated with advanced maternal age and is the nigh common aneuploid condition in liveborn children. It usually results from maternal meiosis I nondisjunction events. ¹³

Nondisjunction results in gametes with either too few or likewise many chromosomes (Fig. 1.iv). The proportion of gametes that are monosomic or triploid after a meiosis I nondisjunction event is one : one. The gametes derived after meiosis II nondisjunction are present in a 2 (euploid):1 (trisomic):ane (nullisomic) proportion. Characterizing disomy is important. Heterodisomy and isodisomy are terms used to describe the parental origin of the extra chromosome in a trisomic gamete. There are important genetic implications that are based on the parental origin of the nondisjunction. The parent of origin of the actress chromosome can be determined by molecular analysis of DNA that makes upward the centromere. When the tetrad fails to disjoin in meiosis I, the subsequent trisomic gamete is considered heterodisomic (homologs originate from a male and a female person parent). When sister chromatids fail to disjoin in meiosis II, the subsequent trisomic gamete is considered isodisomic (homologs are of male or female origin).

Yeast Chromosomes

R.C. Petreaca , in Brenner's Encyclopedia of Genetics (Second Edition), 2013

Chromosome Segregation

Chromosome segregation is another circuitous process because the cell has to ensure that exactly i prepare of duplicated chromosomes is transferred to each of the two cells produced during cell segmentation. In both yeasts, chromosome segregation occurs intranuclearly, meaning that the nuclear envelope does non break down. The cell stage when chromosomes are segregated is known as 'mitosis', which is further subdivided into prophase, metaphase, and anaphase. During an early stage of mitosis known as 'prophase', poly peptide complexes known as condensins interact with chromosomes and facilitate chromosome condensation or compacting. The two sister chromatids produced afterwards replication are held together by specialized proteins known equally cohesins. During 'metaphase', the chromosomes then marshal at the metaphase plate and are captured past microtubules emanating from the spindle, which adhere to the kinetochore that forms on each sister centromere. Complex mechanisms ensure that the chromosomes orient in such a fashion that one sister is captured past microtubules emanating from the daughter cell and the other sister by microtubules from the female parent cell, a process known equally 'biorientation'. After all chromosomes are captured, the cohesin is degraded and one complement of chromosomes are pulled by the microtubules into each of the dividing daughter cell in a jail cell stage known every bit 'anaphase'. Transferring of more or fewer chromosomes than the normal complement is known as chromosome missegregation and leads to 'aneuploidy' (from Greek, meaning 'not the true number'). To preclude missegregation of chromosomes, yeast have evolved all the same some other checkpoint known equally the 'mitotic checkpoint' likewise known equally 'spindle checkpoint' and sometimes 'anaphase checkpoint'. This checkpoint has many functions, including ensuring that chromosomes are properly cohesed, that they are properly aligned at the methaphase plate, that the spindle forms correctly, that each kinetochore is captured by spindle microtubules, that cohesin is properly degraded following capture by microtubules, and that the chromosomes take been correctly segregated into the two dividing cells.

Chromosome segregation has been studied by the mutation of genes that are involved in mitosis followed by observation of chromosome behavior. For example, past studying kinetochore mutants, scientists accept been able to elucidate both the structure of the kinetochore and its function. Drugs that change microtubule function, such every bit nocodazole or thiabendazole (TBZ), are often employed in the report of chromosome segregation. Wild-type cells are non very sensitive to these drugs and tin can tolerate them. Nonetheless, a mutation in a cistron required for chromosome segregation tin increase sensitivity of cells to these drugs. Thus, screens for mutants that are sensitive to these drugs can be conducted to identify genes involved in chromosome segregation. Considering missegregation of even one endogenous chromosome is lethal, chromosome segregation is studied using nonessential artificial chromosomes.

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Chromosome Replication and Segregation

A.C. Leonard , J.E. Grimwade , in Encyclopedia of Microbiology (Third Edition), 2009

Introduction

Chromosome replication and segregation are key events during the microbial prison cell bicycle that must exist completed before a jail cell divides. To reproduce successfully, every jail cell must replicate its chromosome(south) and distinguish nascent sister chromosomes from one another. Each sister chromosome must and then exist physically segregated into one of two new cells prior to completion of cell division. These are not simple tasks considering the big size of microbial genomes (0.2–5   mm) and the extremely express infinite these genomes occupy (0.1–10   μmⁱⁱⁱ). Yet, errors (production of chromosome-less cells) are rare (<x⁻⁵/cell division in Escherichia coli and Saccharomyces cerevisiae). To ensure a low mistake rate, microbial cells require complex and precise regulatory mechanisms for both properly time new rounds of replicative Deoxyribonucleic acid synthesis and orient newly synthesized Deoxyribonucleic acid with respect to fixed intracellular locations. This article is focused on the nature of molecular mechanisms that regulate chromosome replication and segregation in prokaryotic and eukaryotic microorganisms. Most examples will be taken from the bacterium E. coli and the budding yeast S. cerevisiae. Emphasis will be on assembly of Dna–poly peptide complexes at replication origins and localization of specific chromosomal sites during segregation.

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Regulation of Centromeric Chromatin

D. Bade , S. Erhardt , in Chromatin Regulation and Dynamics, 2017

Abstract

Chromosome segregation is cardinal for every living organism to maintain genome stability through mitotic and meiotic divisions. Chromosomes secure their correct segregation by attaching to the mitotic spindle through a large proteinaceous complex called the kinetochore that forms at centromeric chromatin during the onset of mitosis. The composition of centromeric chromatin is significantly different from other chromatin structures and is defined past the presence of the evolutionarily conserved histone H3-variant CENP-A. The topic of this affiliate is the limerick of centromeric chromatin with a special focus on the loading and maintenance of CENP-A, and how its intricate regulation determines the timely formation of functional kinetochores.

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Mitosis and Meiosis Part A

Amitabha Gupta , ... Sue Biggins , in Methods in Cell Biology, 2018

Abstract

Chromosome segregation relies on forces generated by spindle microtubules that are translated into chromosome movement through interactions with kinetochores, highly conserved macromolecular machines that assemble on a specialized centromeric chromatin structure. Kinetochores non only take to stably attach to growing and shrinking microtubules, but they as well need to recruit spindle assembly checkpoint proteins to halt jail cell cycle progression when there are attachment defects. Even the simplest kinetochore in budding yeast contains more than 50 unique components that are nowadays in multiple copies, totaling more 250 proteins in a single kinetochore. The complex nature of kinetochores makes it challenging to elucidate the contributions of individual components to its various functions. In addition, it is hard to manipulate forces in vivo to empathize how they regulate kinetochore–microtubule attachments and the checkpoint. To address these bug, we developed a technique to purify kinetochores from budding yeast that can be used to analyze kinetochore functions and composition besides equally to reconstitute kinetochore–microtubule attachments in vitro.

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Centrosomes and the Art of Mitotic Spindle Maintenance

Edward H. Hinchcliffe , in International Review of Prison cell and Molecular Biology, 2014

one Introduction

Chromosome segregation during mitosis is an essential process that requires absolute fidelity in club for an organism to survive. Chromosome segregation is mediated past polarized microtubules, which equally they enter Thousand-phase of the cell wheel, become remodeled into an antiparallel, bipolar assortment known as the mitotic spindle ( Schrader, 1944, Taylor, 1959; Inoué, 1981; Walczak and Heald, 2008). It is of import to remember that a fundamental characteristic of the mitotic spindle is the interactions between microtubule plus-ends in this bipolarized construction (Wadsworth and Khodjakov, 2004; Tanenbaum and Medema, 2010). Interactions that occur betwixt microtubule-ends help to drive the poles apart, and plant the shape of the spindle. Too, dynamic microtubule plus-ends, emanating from opposite poles, demark to the kinetochores of the sister chromatids (the so-called "amphitelic attachment") and the balance of forces drive chromosome congression to the metaphase plate. Chromosomes that interact with microtubules plus-ends coming from merely a single pole go misaligned, and are said to undergo "syntelic zipper" (Rieder and Salmon, 1998; Salmon et al., 2005).

In animal cells, the major microtubule-organizing center (MTOC) is established by the centrosome, an organelle that consists of a pair of centrioles surrounded by a matrix of pericentriolar cloth (PCM: Gould and Borisy, 1977; Wiese and Zheng, 1999). The nucleation of new microtubules from the MTOC is mediated by the gamma-tubulin ring complexes (γ-TURCs), which are embedded within the PCM of the centrosome (Dictenberg et al., 1998; Takahashi et al., 2002; Lüders and Stearns, 2007). This arrangement generates the polarized microtubule array, with the minus-ends at the cell center and the plus-ends at the jail cell periphery. The size of the centrosome remains relatively constant from jail cell to cell within a population: during One thousand₁, in that location is a single pair of centrioles inherited following mitosis, and the bulk of the PCM is concentrated effectually the older (mother) centriole (Hinchcliffe, 2003; Sluder and Khodjakov, 2010). As the cell cycle progresses from One thousand₁ into Southward-phase, each preexisting centriole nucleates a single daughter centriole, or procentriole, at right angles to itself (Figure vi.1). The replication of these centrioles underlies the one-to-ii duplication of the centrosome as a whole, and increases the amount of PCM present at the centrosome (Hinchcliffe and Sluder, 2001a; Nigg, 2007; Strnad and Gönczy, 2008). In preparation for mitosis, the pairs of duplicated centrioles split apart and dissever (Effigy vi.2), each daughter centrosome remains associated with at to the lowest degree some of the interphase microtubule network, causing this network to split into ii (Mazia, 1987; Rosenblatt, 2005; Hinchcliffe, 2011). Every bit the two centrosomes segregate apart, the single MTOC becomes two foci, and the nucleating capacity of each centrosome increases via a cell bicycle-dependent aggregating of γ-TURCs (Dictenberg et al., 1998; Khodjakov and Rieder, 1999; Haren et al., 2009; Zhang et al., 2009; Lee and Rhee, 2011). The increment in microtubule nucleating capacity is coupled to the increased dynamics of microtubules during mitosis (Job et al., 2003). The upshot is that at the time of nuclear envelope breakup (Nib), there are ii MTOCs, with dynamic MT plus-ends that interact toward the cell centre. These MTOCs are steadily pushed and pulled apart by the antiparallel nature of the nascent spindle and microtubule interactions with the cell cortex (Wadsworth and Khodjakov, 2004). As the chromosomes condense and are released from the nuclear envelope they also encounter these microtubule plus-ends, which bulldoze chromosome congression to the prison cell center (or whichever position in the cell is destined to define the metaphase plate). It is the splitting/separation of the MTOC prior to NEB—a procedure that depends on the regulated centriole duplication which provides the basis for the statement that the centrosome is responsible for establishing the bipolarity of the mitotic spindle in mammalian somatic cells (Hinchcliffe and Sluder, 2001a).

Figure 6.ane. Centriole pairs. (a) Transmission electron micrograph of an intact diplosome. Note the nine triplet microtubules in the aeroplane of sectioning. (b) Fluorescence microscopy epitome of a mother-daughter centriole pair. The mother is shown in negative relief as a "doughnut" of anti-g tubulin staining (light-green); the dark center contains the centriole proper. The nascent girl centriole is depicted by the region of SAS-6/Bld-12p staining (red). Bar in a   =   200   nm; in b   =   ane   μm. (For interpretation of the references to color in this figure legend, the reader is referred to the online version of this book.)

Figure half-dozen.two. Centriole duplication and spindle pole assembly. Five cells illustrating the stages of centriole duplication and the formation of the bipolar spindle. (a) 2 cells, the upper is in G1 (pair of centrioles indicated by the anti-centrin-two staining in red) and the lower in S-phase, having undergone centriole duplication (two pairs of centrin-two foci). Each cell contains simply 2 anti-g tubulin foci. Note the increase in DAPI label in the S-phase prison cell. (b) G2 cell, with a pair of duplicated centrioles associated with a pocket-size MTOC. (c) Prophase cell, where the two pairs of centrioles have disjoined and are in the process of separating. Each is associated with a microtubule aster. (d) Prometaphase cell, with a pair of centrioles associated with each pole. Bar   =   five   μm. (For interpretation of the references to color in this figure legend, the reader is referred to the online version of this book.)

Centrosomes role in a dominant role during the institution of spindle polarity. For example, abnormal centrosome number (>2 per jail cell at the onset of mitosis) tin pb to mitotic defects via alterations in spindle arrangement (Sluder and Nordberg, 2004; Ganem et al., 2007). Indeed, many cancer cells are found to have more than than two centrosomes, and this increase correlates with the severity of the disease (Pihan et al., 2003; Holland and Cleveland, 2009). While initial observations suggested that abnormal centrosome number caused multipolar spindles and genome fragmentation, current models suggest that the situation is more complex (Gordon et al., 2012; Silkworth and Cimini, 2012). Cells containing multiple centrosomes tin course bipolar spindles with clustered centrosomes at each pole; these spindles prove an increased frequency of improper microtubule–kinetochore interactions, such as merotelic attachments, which pb to chromosome segregation defects and aneuploidy (Quintyne et al., 2005; Gordon et al., 2012; Silkworth and Cimini, 2012).

It is clear that the centrosome does exert a dominant activity on spindle pole assembly, and influences the polarity of the spindle when present (Mazia et al., 1960; Heald et al., 1997; Hinchcliffe, 2011; Moutinho-Pereira et al., 2013). However, an unqualified office of the centrosome in establishing and maintaining spindle bipolarity remains controversial. This uncertainty exists considering the organelle is non admittedly required to build a spindle, even in cells that usually comprise centrosomes. Over the last xxx+ years, studies in early on embryonic systems, Xenopus egg extracts, Drosophila cells, and even experimentally manipulated mammalian somatic cells have revealed an acentriolar spindle assembly pathway (Steffen et al., 1986; Zhang and Nicklas, 1995; Heald et al., 1996; Wilde and Zheng, 1999; Ohba et al., 1999; Kaláb et al., 1999; Carazo-Salas et al., 1999; Khodjakov et al., 2000; Megraw et al., 2001; Hinchcliffe et al., 2001). In fact, the pioneering studies in Xenopus revealed a novel biochemical network that influences mitotic spindle assembly, based on the small GTPase RAN, which becomes activated in the vicinity of chromatin (Wilde et al., 2001; Carazo-Salas et al., 2001). The acentriolar spindle assembly pathway (besides known equally the chromatin-mediated spindle assembly pathway) depends on the interaction of chromatin with randomly oriented microtubules (Walczak and Heald, 2008). There as well appears to be a significant contribution to the acentriolar spindle assembly pathway past microtubules that assemble de novo (Wadsworth and Khodjakov, 2004). While the discovery and characterization of the acentriolar spindle assembly pathway are obviously important, this pathway has been proposed as a potential—and highly seductive—global mechanism that reconciles centrosomal and acentrosomal spindle assembly. However, recent data advise that the chromatin-mediated pathway does not play a meaning role during the very early on events of spindle assembly, when polarity is first established (Hornick et al., 2011). Vertebrate somatic cells and oocytes, likewise as country plants all generate spindle bipolarity past organizing their microtubule arrays well before the onset of NEB, and thus, have few free microtubules to interact with condensed chromosomes exposed after the dissolution of the nuclear envelope.

These observations advise that the centriole-containing centrosomes practise indeed play an of import office in ensuring that spindle associates occurs with the proper polarity, in cells that unremarkably contain them. But this piece of work stands in stark contrast to equally compelling studies that conclude that the centriole-containing centrosome are non the main drivers of spindle assembly during mitosis (Megraw et al., 2001; Mahoney et al., 2006; Basto et al., 2006; Courtois et al., 2012; Azimzadeh et al., 2012; Moutinho-Pereira et al., 2013). In society to reconcile these differing views, I volition first briefly describe the associates and part of the centrosome, and the two pathways (centriolar vs. acentriolar) used for spindle assembly.

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Mitosis and Cytokinesis

In Cell Biology (Tertiary Edition), 2017

Chromosome segregation is similar in plants and animals, but cytokinesis is very different because plants lack myosin-II and do not form a conventional contractile band ( Fig. 44.26). Myosin-Two appeared during evolution in the common ancestor of amoebas, fungi and animals, after branching from plants (run across Fig. two.4B). Plants also lack dynein, so microtubule dynamics in mitosis are regulated by some of the more than 20 different plus-end– and minus-stop–directed kinesins that are expressed in mitotic cells. In a further difference from animals, plants also lack centrosomes, and during interphase, microtubules radiate out from the surface of the cell nucleus in all directions. In mitosis, the spindle does not focus to abrupt poles at metaphase; instead, it assumes a barrel shape with broad, apartment poles. Early on in mitosis, a ring of microtubules and actin filaments forms around the equator of the cell next to the nucleus. This so-called preprophase band disassembles as cells enter prometaphase. Considering the entire prison cell cortex is covered by a meshwork of actin filaments, disassembly of the preprophase ring really leaves an actin-poor zone in a ring where cytokinesis will ultimately occur. This is called the cortical division site, and information technology is marked by the tethering of specific kinesin motors. In late anaphase, two nonoverlapping, antiparallel arrays of microtubules form over the primal spindle. This structure, the phragmoplast, gradually expands laterally until information technology makes a mirror-symmetric double disk of short microtubules oriented parallel to the spindle axis with their plus ends abutting the aeroplane of prison cell cleavage. Golgi vesicles, containing cell wall materials (see Fig. 32.xiii), move along phragmoplast microtubules to the equator, where they fuse due to the action of cytokinesis-specific soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) proteins (meet Fig. 21.15), forming a membrane network that becomes the new plasma membrane and laying down the material that will become the new cell wall. Dynamin-related proteins as well participate in shaping the newly forming plasma membrane. Thus, the membrane fusion machinery used for cytokinesis by eukaryotes likely came from the last eukaryotic common antecedent. Actin filaments polymerized by formins and myosin-Eight help position the phragmoplast in the cell. As the zone of newly deposited membrane expands radially, the band of microtubules surrounding it similarly expands. Somewhen, the new membrane reaches the lateral jail cell periphery, and fusion with the plasma membrane separates the ii girl cells. The cortical division site, not the spindle, determines the site of cleavage. This was shown by centrifuging mitotic cells to displace the spindle from the central location where information technology initially formed. Tardily in mitosis, the phragmoplast formed at the midzone of the displaced spindle, but this phragmoplast and then migrated to the airplane of the preprophase band, where cytokinesis occurred. Since plant cells have cell walls and practise not motion, the orientation of cleavage planes critically determines the morphology of the organism. The hormone auxin can influence cleavage, giving ascension to asymmetric division of girl cells, merely the underlying mechanism is not yet known.

Figure 44.26. CYTOKINESIS IN College PLANTS.

Run into the text for details.

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Prison cell and Molecular Biology of Septins

Karen Y.Y. Fung , ... William S. Trimble , in International Review of Jail cell and Molecular Biology, 2014

4.ii.1 Chromosome segregation

Proper chromosome segregation is mediated past kinetochores, which allow for the attachment of the microtubule based mitotic spindle to the aligned chromosomes at the cell equator. Centromere protein E (CENP E) is a microtubule based kinetochore motor protein that stabilizes and positions the chromosome, ensuring right attachment by the mitotic spindle. CENP E also serves as part of the mitotic checkpoint mechanism which delays the next step of the cell cycle when replication errors are detected, allowing for the correction of the error. The cell cycle machinery and progression are heavily regulated by phosphorylation of key proteins and a disquisitional regulator is Aurora B. SEPT1 ( Qi et al., 2005), SEPT2, SEPT6 (Spiliotis et al., 2005), and SEPT9 (Nagata et al., 2003) were establish to be localized to the mitotic spindles. Furthermore, Septins have been found to be involved in the localization of CENP East to kinetochores (Zhu et al., 2008). Depletion of septins led to delays in chromosome congression and degradation, consistent with a function in scaffolding CENP E to kinetochores (Spiliotis et al., 2005).

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Mechanisms of Dna Recombination and Genome Rearrangements: Methods to Written report Homologous Recombination

Ying Wai Chan , Stephen C. West , in Methods in Enzymology, 2018

Abstract

Successful chromosome segregation depends on the timely removal of DNA recombination and replication intermediates that interlink sister chromatids. These intermediates are acted upon past structure-selective endonucleases that promote incisions close to the junction point. GEN1, a member of the Rad2/XPG endonuclease family, was identified on the footing of its power to cleave Holliday junction recombination intermediates. Resolution occurs by a nick and counter-nick mechanism in strands that are symmetrically related across the junction point, leading to the formation of ligatable nicked duplex products. The deportment of GEN1 are, however, not restricted to HJs, as 5′-flaps and replication fork structures besides serve as excellent in vitro substrates for the nuclease. In the cellular context, GEN1 action is observed late in the cell cycle, as most of the protein is excluded from the nucleus, such that information technology gains access to Deoxyribonucleic acid intermediates after the breakdown of nuclear envelope. Nuclear exclusion ensures the protection of replication forks and other DNA secondary structures important for normal metabolic processes. In this chapter, nosotros describe the purification of recombinant GEN1 and detail biochemical assays involving the use of synthetic DNA substrates and cruciform-containing plasmids.

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How Mitotic Errors Contribute to Karyotypic Variety in Cancer

Joshua K. Nicholson , Daniela Cimini , in Advances in Cancer Research, 2011

A Kinetochore–Microtubule Attachments

Accurate chromosome segregation is ensured by the attachment of the two sister chromatids to microtubules from opposite spindle poles (amphitelic zipper; Fig. 4A ). Yet, other types of attachments can and do occur in mitosis. These include monotelic, syntelic, and merotelic attachment (Fig. fourB–D)..

Fig. four. Types of kinetochore–microtubule attachments.

Iv different types of attachments can exist formed during the early stages of mitosis. These include amphitelic, monotelic, syntelic, and merotelic attachments. (A) Amphitelic attachments are divers by the zipper of the two sister kinetochores to microtubules from opposite spindle poles. This type of attachment is necessary for accurate chromosome segregation. (B) Monotelic attachment occurs when one of the two sister kinetochores of an individual chromosome is attached to one spindle pole whereas the other sister is unattached. (C) Syntelic attachment occurs when the 2 sister kinetochores of an individual chromosome bind microtubules from the same spindle pole. (D) Merotelic attachment occurs when a single kinetochore binds microtubules from two poles rather than simply i. See the text for further details.

Monotelic attachment occurs when one of the two sister kinetochores of an individual chromosome is fastened to i spindle pole whereas the other sister is unattached (Fig. 4B). This type of attachment is very common in early mitosis, and it is known to trigger a checkpoint-dependent mitotic delay (Rieder et al., 1994, 1995). Thus, if the mitotic checkpoint is functional (run into beneath for a more specific discussion of mitotic checkpoint and cancer), monotelic kinetochore attachment will not contribute to cancer karyotypic diversity.

Syntelic attachment occurs when the ii sister kinetochores of an individual chromosome bind microtubules from the same spindle pole (Fig. 4C). Syntelic attachments are non commonly observed in untreated cells (Hauf et al., 2003), and there are no reports of increased frequencies of syntelic attachments in cancer cells, suggesting that syntelic zipper does non play an of import role in cancer cell chromosome mis-segregation.

Finally, merotelic attachment occurs when a unmarried kinetochore binds microtubules from ii poles rather than just one [Fig. 4D; (Cimini et al., 2001; Ladrach and LaFountain, 1986)]. Merotelic attachments occur frequently in early mitosis (Cimini et al., 2003) and can exist corrected via an Aurora B-dependent mechanism prior to anaphase onset (Cimini, 2007; Cimini et al., 2006; DeLuca et al., 2006). Nevertheless, merotelic attachments exercise non induce a SAC-dependent mitotic filibuster (Cimini et al., 2002, 2004; Khodjakov et al., 1997; Wise and Brinkley, 1997; Yu and Dawe, 2000), and thus they can persist into anaphase, at which time their behavior will depend on the relative size of the microtubule bundles jump to the individual kinetochore [Fig. v; (Cimini et al., 2004) reviewed in (Cimini, 2008; Gregan et al., 2011)]. If the two microtubule bundles attached to a merotelic kinetochore are unlike in size, during anaphase the chromosome will be shifted to the side fastened to the thicker parcel [Fig. 5A; (Cimini et al., 2004)]. Conversely, if the ii microtubule bundles are comparable in size, the merotelically attached chromosome will lag backside at the spindle equator while all the other chromosomes segregate to contrary spindle poles [Fig. vB; (Cimini et al., 2001, 2004)]. Although the experimental observations on the fate of these anaphase lagging chromosomes are relatively express (Cimini et al., 2002; Utani et al., 2010), they seem to advise that the lagging chromosome can end upward in either 1 of the ii daughter cells, depending on where the cleavage furrow ingresses with respect to the lagging chromosome (Fig. 5B, middle and correct panels). These experiments (Cimini et al., 2002; Utani et al., 2010) likewise suggest that anaphase lagging chromosomes form micronuclei upon mitotic exit (Fig. 5B, right panels). Interestingly, micronuclei are frequently observed in cancer cells (Brogger et al., 1990) and correspond a biomarker for increased risk of cancer [(reviewed in (Fenech, 2002; Majer et al., 2001)]. Although some micronuclei may incorporate chromosome fragments rather than entire chromosomes, information technology is noteworthy that a number of studies take shown that anaphase lagging chromosomes are oft observed in cancer cells (Ganem et al., 2009; Gisselsson et al., 2005; Reing et al., 2004; Saunders et al., 2000; Silkworth et al., 2009; Thompson and Compton, 2008), and can possibly represent the virtually common type of chromosome mis-segregation in CIN cancer cells [reviewed in (Cimini and Degrassi, 2005; Compton, 2011)]. Notably, mutations in (or depletion of) certain genes traditionally classified as oncogenes or tumor suppressor genes cause defects that lead to merotelic attachments and anaphase lagging chromosomes. For instance, truncation of the adenomatous polyposis coli (APC) factor or depletion of the APC protein causes anaphase lagging chromosomes (Draviam et al., 2006; Green et al., 2005; Green and Kaplan, 2003). Similarly, a recent series of studies showed that the retinoblastoma poly peptide (pRb) plays an important office in mitosis and its depletion results in abnormal chromosome condensation (Coschi et al., 2010), centromere dysfunction (Manning et al., 2010), chromatid breaks, and cohesion defects (van Harn et al., 2010), which can in turn lead to merotelic attachment and anaphase lagging chromosomes (Manning et al., 2010; Sage and Straight, 2010).

Fig. 5. Possible fates of merotelically fastened anaphase lagging chromosomes.

Merotelic attachments do non induce a SAC-dependent mitotic delay, and thus they can persist into anaphase, at which time their behavior will depend on the relative size of the microtubule bundles jump to the individual kinetochore. If the two microtubule bundles attached to a merotelic kinetochore are different in size (A), during anaphase the chromosome will be shifted to the side attached to the thicker bundle. Conversely, if the two microtubule bundles are comparable in size (B), the merotelically attached chromosome will lag behind at the spindle equator while all the other chromosomes segregate to contrary spindle poles. Upon mitotic exit, the lagging chromosome forms a micronucleus. See the text for farther details.

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