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ScienceWeek
CELL BIOLOGY: ON CHROMOSOME SEGREGATION
The following points are made by Tarun M. Kapoor (Current Biology 2004 14:R1011):
1) The faithful transmission of genomes to daughter cells requires that each replicated chromosome is correctly transported during cell division. Chromosome movements are achieved through attachments of kinetochores -- proteinaceous complexes assembled on centromeric DNA -- to microtubules from the bipolar spindle-shaped cell-division apparatus. For accurate segregation, it is generally believed that a kinetochore must attach to microtubules from one spindle pole, while the sister kinetochore must attach to microtubules from the opposite pole; this is referred to as amphitelic attachment or chromosome bi-orientation [1-3].
2) During mitosis, these kinetochore-microtubule attachments are established in the period between nuclear envelope breakdown and anaphase, two irreversible events in vertebrate mitosis [1,4]. Most current models suggest that errors in chromosome attachment are corrected before anaphase by the reversal of improper attachments [1,3]. If improper attachments are not corrected, they may result in whole chromosome loss. New work by Cimini et al [5], provides direct evidence for how one type of improper chromosome-microtubule attachment may be corrected in mammalian cells. There are number of surprising results in this study, including data showing that a chromosome can segregate correctly while maintaining improper attachments, and that this mechanism is active after the start of anaphase, a point-of-no-return during mitosis.
3) The formation of correct chromosome-microtubule attachments passes through an "on-pathway" intermediate state of monotelic attachment, or chromosome mono-orientation, in which one sister kinetochore is attached to microtubules from a spindle pole while the other kinetochore is unattached [2]. The pathway is not error free, and a number of types of "off-pathway" intermediates have also been characterized. In merotelic attachment, for example, one sister kinetochore has microtubules connecting it to both spindle poles; the other sister kinetochore is often attached to only one of the two spindle poles. This error can only occur in organisms that have more than one microtubule binding site per kinetochore. In syntelic attachments, both sister kinetochores are attached to the same spindle pole [2]. If any of these on-pathway or off-pathway intermediates in chromosome attachments remain uncorrected during cell division, chromosomes will be lost.
4) Distinguishing between monotelic and amphitelic attachment is conceptually simple. If a kinetochore has a finite number of microtubule binding sites, the occupancy of each binding site can be determined. If any unoccupied binding sites are present, an error can be signaled. Components of the spindle assembly checkpoint -- a signaling pathway that can delay anaphase and contribute to proper chromosome segregation -- are targeted to kinetochore sites not occupied by microtubules [1]. The displacement of these proteins from kinetochores by microtubules can satisfy the checkpoint and thereby release the block to anaphase. The anaphase delay allows time for chromosome position to be altered and centrosome-dependent and centrosome-independent pathways, with different kinetics, to operate until monotelic attachments are converted to proper amphitelic attachments.
References (abridged):
1. Rieder, C.L. and Salmon, E.D. (1998). The vertebrate cell kinetochore and its roles during mitosis. Trends Cell Biol. 8, 310-318
2. Ault, J.G. and Rieder, C.L. (1992). Chromosome mal-orientation and reorientation during mitosis. Cell Motil. Cytoskeleton 22, 155-159
3. Nicklas, R.B. (1997). How cells get the right chromosomes. Science 275, 632-637
4. Kapoor, T.M. and Compton, D.A. (2002). Searching for the middle ground: mechanisms of chromosome alignment during mitosis. J. Cell Biol. 157, 551-556
5. Cimini, D., Cameron, L.A. and Salmon, E.D. (2004). Anaphase spindle mechanics prevent mis-segregation of merotelically-oriented chromosomes. Curr. Biol. 14:2149
Current Biology http://www.current-biology.com
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ON CHROMOSOME MECHANICS
Notes by ScienceWeek:
In biology, the full cycle from nondividing cell to dividing cell to nondividing daughter cells is called the "cell cycle". In a nondividing biological cell, DNA and its associated proteins are loosely packed, forming a network called "chromatin". During cell division, DNA and certain proteins condense and coil into rod-shaped bodies called "chromosomes". Because of the coiling, chromosomes contain a large amount of DNA relative to their size.
Each chromosome is apparently a single DNA molecule, highly folded and coiled, combined with a variety of protein molecules. This is the general DNA architecture for all living cells, but cells with internal organelles such as a nucleus (eukaryotes) and cells without such organelles (prokaryotes) differ in further complexities. Through an electron microscope, chromatin in eukaryote cells appears as "beads-on-a-string". Each bead is a "nucleosome", consisting of double-stranded DNA wrapped twice around a core of 8 proteins (*histones). The string between the beads is called "linker DNA".
The nucleosomes are folded into a larger structure called a "chromatin fiber", and these fibers in turn fold into large loops. In cells that are not dividing, this is the extent of DNA packing. Before cell division, the DNA duplicates and the chromatin strands subsequently shorten and coil even further to form "chromatids". During the cell division cycle, a pair of chromatids ("sisters") makes a new chromosome, two identical sets of chromosomes are mechanically separated by a specialized macromolecular apparatus (*spindle apparatus), the entire cell cleaves into two daughter cells, and cell division is thus completed. An apparently simple scheme in summary, but surely one of the wonders of the natural world.
The following points are made by Tatsuya Hirano (Genes & Development 1999 13:11):
1) The dynamic behavior of chromosomes was described by cytologists long before the central role of DNA as the genetic material was recognized, and long before the biochemical basis of cell cycle progression was elucidated. Nevertheless, the molecular mechanisms underlying the structural changes of chromosomes during the cell cycle have remained poorly understood.
2) A recent breakthrough in this field was the discovery of a new family of chromosomal *ATPases, called the "structural maintenance of chromosomes" family (SMC family) that are apparently involved in chromosome condensation and adhesion. These proteins are large polypeptides between 1000 and 1500 amino acids long that share in common several structural motifs.
3) SMC proteins are apparently key components that regulate a wide variety of chromosomal events from bacteria to humans. Although recent studies have uncovered diverse cellular functions and unique biochemical activities of these new chromosomal ATPases, we still do not understand how they are functionally related and mechanistically linked.
4) The author suggests that ATP-modulated cross-linking of DNA represents the key mechanism underlying all actions of SMC proteins, and that in eukaryotes, combinatorial association of different SMC and non-SMC subunits allows each SMC protein complex to acquire specialized cellular functions.
Genes & Development http://www.genesdev.org
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Notes by ScienceWeek:
histones: The nucleosome is a tertiary structure of chromosomal DNA found in eukaryotic cells. In chromosomes, about every 200 nucleotides, the DNA double helix is coiled around a complex of 8 histone proteins, the entire assembly having the appearance of beads on a string. The beads of nucleosomes are in turn supercoiled into a solenoid structure, and the entire complex of the eukaryotic chromosome is called "chromatin".
The small histones proteins are basic (as opposed to acidic) proteins, and they are essential in forming nucleosomes. The nucleosomes are apparently one of the key elements in the solution to the DNA packing problem. The packing problem can be stated as follows: Were the DNA contained in a typical cell nucleus extended, it would measure a meter or more in length.
Since the nucleus itself is usually no more than 5 to 10 micrometers in diameter, there is a topological problem in the packing of the enormous length of DNA into a volume 6 orders of magnitude less than the extent of the molecule. The topological packing problem is solved by systematic and repeated foldings of the DNA molecule in conjunction with nuclear protein molecules that bind to DNA and fold it into chromatin fibers.
Our understanding of the details of these molecular arrangements essentially began with the x-ray diffraction observations by Wilkins in the late 1960s that purified chromatin fibers show a repeating structure with a periodicity of 10 nanometers. A decade later, new methods of preparation of chromatin for the electron microscope provided the first visualization of the nucleosome "beads-on-a-string" structure.
spindle apparatus: (mitotic spindle) A microtubule apparatus appearing during cell division. Microtubules are part of the cytoskeleton of biological cells, the quasi-rigid matrix that among other things determines cell shape. The microtubules are 25 nanometers in diameter, and composed of the protein tubulin. They occur in regular arrays in cilia, flagella, the mitotic spindle, and in the cytoplasm in general, and they contribute not only to cell shape, but also to cell motility. In the case of cell division, the microtubules apparently generate a sliding force that results in the pushing and pulling of cell components and the eventual pulling apart of the two poles of the cell.
ATPases: ATP (adenosine triphosphate) is the most important chemical energy source in all living cells, intimately involved in various cell functions and cell metabolism, and an entity in numerous cyclic chemical pathways involved in the synthesis of components. An ATPase is an enzyme that catalyzes the hydrolysis of adenosine triphosphate to adenosine diphosphate and orthophosphate.
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CELL BIOLOGY: ON EUKARYOTIC CHROMOSOME EVOLUTION
The following points are made by E.E. Eichler and D. Sankoff (Science 2004 301:793):
1) Chromosomes evolve by the modification, acquisition, deletion, and/or rearrangement of genetic material. Defining the forces that have affected the eukaryotic genome is fundamental to our understanding of biology and evolution (species origin, survival, and adaptation). Chromosomal evolution includes a continuum of molecular-based events of greatly varied scope. For historical and methodological reasons, complete integration of these different levels of chromosomal structural change has not been practical.
2) Evolutionary biologists have approached genome evolution from two different perspectives. The holistic view compared the number of chromosomes and the order of fragments (homologous segments) among closely and distantly related species by using genetic mapping tools and in situ methods (1). These studies provided a framework for understanding the nature and pattern of chromosomal rearrangement among eukaryotic species. However, because of limitations in resolution, these studies provided little insight into the underlying mechanisms responsible for such changes, and they were not adequate for assessing less conserved regions.
3) The alternate, reductionist perspective has focused on analysis corresponding to small blocks of DNA sequence. Through comparative sequencing among closely related species, considerable diversity of mutational events has been inferred. Such inferences, however, are restricted to regional analyses of DNA and, by their very nature, are limited.
4) With the advent of large-scale sequencing of eukaryotic genomes, a bridge connecting these two perspectives is emerging. Comparative analyses of complete genomes can provide a comprehensive view of large-scale changes in synteny, gene order, and regions of nonconservation while simultaneously affording exquisite molecular resolution at the level of single-base pair differences. Knowing the precise sequence at regions of rearrangement gives insight into underlying molecular mechanisms. New computational methods can be developed to effectively digest and model these vast quantities of data. As a result of this genomic revolution, novel approaches and insights into the patterns and mechanisms of both small- and large-scale chromosomal rearrangement are beginning to emerge.
5) In summary: Large-scale genome sequencing is providing a comprehensive view of the complex evolutionary forces that have shaped the structure of eukaryotic chromosomes. Comparative sequence analyses reveal patterns of apparently random rearrangement interspersed with regions of extraordinarily rapid, localized genome evolution. Numerous subtle rearrangements near centromeres, telomeres, duplications, and interspersed repeats suggest hotspots for eukaryotic chromosome evolution. This localized chromosomal instability may play a role in rapidly evolving lineage-specific gene families and in fostering large-scale changes in gene order. Computational algorithms that take into account these dynamic forces along with traditional models of chromosomal rearrangement show promise for reconstructing the natural history of eukaryotic chromosomes.(2-5)
References (abridged):
1. S. J. O'Brien et al., Science 286, 458 (1999)
2. Arabidopsis Genome Initiative, Nature 408, 796 (2000)
3. S. Aparicio et al., Science 297, 1301 (2002)
4. J. H. Nadeau, B. A. Taylor, Proc. Natl. Acad. Sci. U.S.A. 81, 814 (1984)
5. International Human Genome Sequencing Consortium, Nature 409, 860 (2001)
Science http://www.sciencemag.org
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