240 kb to several Mb
FIGURE 7-8 Centromere size and com -position varies dramatically between different organisms. 5. cerevisiae centromeres are small And composed of non-repetitive sequences. In contrast the centromeres of other organisms such as the fruit fly, Drosophila melonogoster, and the fission yeast, Schtzcsocchammyces pom be, are mudi larger and are largely composed of repetitive sequences. Only the central 4-7 kb of the $ poenbe centromere is non-repetitive and the targe majority of the Drosophila and Human centromeres ate repetitive ONA.
ism to organism. This repeat is typically composed of a short TG-rich repeat. For example, human telomeres have the repeating sequence of S'-TTAGGG-3', As we will sec in Chapter 8, the repetitivo nature of telomeres is a consequence of their unique method of replication.
Eukaryotic Chromosome Duplication and Segregation Occur in Separate Phases of the Cell Cycle
During cell division, the chromosomes must be duplicated and segregated into the daughter cells. In bacterial colls these events occur simultaneously. That is, as the DNA is replicated, ihe resulting two copies arc separated into opposite sides of tbn cell. Although it is dear that these events are tightly regulated in bacteria, the details of how this regulation is achieved are poorly understood. In contrast, eukaryotic ceils duplicate and segregate their chromosomes at distinct times during ccll division. We will focus on these events for the remainder of our discussion of chromosomes.
The events required for a single round of cell division are collectively known as the ceil cycle. Most eukaryotic cell divisions maintain the number of chromosomes in the daughter cells that were present in the parental ccll. This type of division is called mitotic cell division.
The mitotic cell cycle can be divided into four phases: Gl, S, G2, and M (Figure 7-10). The key events involved in chromosome
FIGURE 7-9 The structure of a typical telomere. The repeated sequence (from human cells) is shown in a representative box. Note that the region of ssDNA at the 3' end ol the chromosome can be hundreds of b?ses long.
FIGURE 7-10 The eukaryotic mitotic cell cycle. 1 here are four stages of the eukaryotic cell cycle. Chromosomal replication occurs during S phase and chromosome segregation occurs during M phase. The C1 and G2 gap phases allow the cell to prepare for the next events in the cell cycle. For example, many eukaryotic cells use the G1 phase of the cell cyde to establish that the level of nutrients is sufficiently high to allow the completion of cell division prepare for chromosome segregation chromosome segregation
prepare for chromosome segregation chromosome segregation
DNA replication prepare tor cell division
DNA replication prepare tor cell division propagation occur at distinct times during the cell cycle. DNA synthesis occurs during the synthesis, or S phase, of the cell cycle, resulting in the duplication of each chromosome (Figure 7-11). Each chromosome of the duplicated pair is callcd a chromatid, and the two chromatids of a given pair are called sister chromatids. Sister chromatids are hold together after duplication through the action of a molecule called cohesin, which we describe below. The process thai holds them together is called sister chromatid cohesion and this tethered state is maintained until the chromosomes segregate horn one another.
Chromosome segregation occurs during mitosis or the M phase of the cell cycle. We will consider the overall process of mitosis below, bul first we locus on three key steps in the process (Figure 7-12). First, each pair of sister chromatids is bound to a structure called the mitotic spindle. This structure is composed of long, protein fibers called microtubules that are attached to one of the two microtubule organizing
two major chromosomal events occur during S phase. DMA replication copies each chromosome completely, and shortly after replication has occurred, sister chromatid cohesin is established by placing nng-shaped cohesin molecules around the two copies of the recently replicated DNA. Each blue or red "tube" represents an ssDNA molecule.
key events in S phase initiation Of DNA replication initiation Of DNA replication
organizing center key events in M phase kinelocbore destroy cohesin destroy cohesin
FIGURE 7-12 The events of mitosis (M phase). Three major events occur during mitosis, First, the two kinetochores of each linked sister-chromatid pair attach to opposite poies of the mitotic spindle Once all knetotborei. are bound to opposite poies, sister chromatid cohesion is eliminated by destroying [lie coiit?,in (ing, Finally, aft?» cohesion re eliminated, ttie set« diromatids ate tegregaietl to opposite potes oi ttie mitotic spindle.
centers (also caller! centrosomes in an i ma I cells or spindle pole bodies in yeasts and other fungi). The microtubule organizing centers are located on opposite sides of the ceil forming "pules" toward which the microtubules pull the chromatids. Chromatid attachment is mediated by the kinetochore assembled at each centromere (Figure 7-6). Second, the cohesion between the chromatids is dissolved. Before cohesion is dissolved, it resists the pulling forces of the mitotic spindle. After cohesion is dissolved, (he third major event in mitosis can occur: sister chromatid separation. In the absence of the counterbalancing force of chromatid cohesion, the chromatids are rapidly pulled toward opposite poles of this mitotic spindle. Thus, cohesion between the sister chromatids and attachment of sister chromatid kinetochoies to opposite poles of the mitotic spindle play opposing roles ihat must be carefully coordinated tor chromosome segregation, tu occur properly.
Chromosome Structure Changes as Eukaryotic Cells Divide
As chromosomes proceed through a round of cell division, their structure is altered numerous times; however, there are two main states for the chromosomes (Figure 7-13). The chromosomes are in their most compact form as cells proceed through mitosis or meiosis. The process that results in this compact form is called chromosome condensation. In this condensed state the chromosomes are completely disentangled from one another, greatly facilitating the segregation process.
During the Gl, S, and G2 phases (collectively referred to as interphase), the chromosomes are significantly less compact. Indeed, at these stages of the eel! cycle, the chromosomes are likely to be highly intertwined, resembling more of a plate of spaghetti than the organized view of chromosomes during mitosis. Nevertheless, even during these stages the structure of the chromosomes change. DNA replication
FIGURE 7-13 Changes in chromatin structure. Chromosomes are maximalty condensed in M phase and ¿«condensed throughout the rest of the celf cycle (C1,S, and G2 in mitotic celts) Togethei these decondensçd slages are referred to as interphase.
DNA replication requires the nearly complete disassembly and reassembly of the proteins associated with each chromosome. Immediately after DNA replication, sister-phromatid cohesion is established, linking the newly replicated chromatids to une another. As transcription of individual genes is turned on and off or up and down, there are associated changes in the structure of the chromosomes in those regions occurring throughout the coll cycle. Thus, the chromosome is a constantly changing structure that is more like an organelle than a simple string of DNA.
Sister Chromatid Cohesion and Chromosome Condensation Are Mediated by SMC Proteins
The key proteins thai mediate sister chromatid cohesion and chromu-some condensation are related to one another. The structural maintenance of chromosome (SMC) proteins are extended proteins that form defined pairs by interacting through lengthy coiled-coil domains (see Chapter 5). Together with non-SMC proteins they form multiprolein complexes that act to link two DNA helices together. An SMC-protein-containing complex called cohesin is required to link the two daughter DNA duplexes (sister chromatids] together after DNA replication. It is this linkage that is the basis fur sister chromatid cohesion. The structure of cubes in is thought to be a large ring composed of two SMC proteins and a third non-SMC protein. Indeed, there is growing evidence that the mechanism of sister chromatid cohesion is that both daughter chromosomes pass through the center of the cohesin protein ring (Figure 7-14). In this model, proteolytic cleaveage of the non-SMC subunît of cohesin results in the opening of the ring and the loss of cohesin.
The chromosome condensalion that accompanies chromosome segregation also requires a related SMC-containing-complex called condensin. Although less is known about the structure and function of this complex, it shares many of the features of the cohesin complex, suggesting that it too is a ring-shaped complex. If so, it may use its ring-like nature to induce chromosome condensation. For example, by [inking different regions of the same chromosome together condensin could readily reduce the overall linear length of the chromosome (Figure 7-14).
FIGURE 7-14 A speculative mode) for the structure of cohesins and condensing
Cohesins and condensins are components of the nudear scaffold Both play important rdes in bringing distant or different regions of PNA together. "Hie proposed ring-shaped structure of these proteins would allow a flexible, but strong Unit between two regions of DMA. in this illustration, the SMC proteins are shown as green (coheyn) or blue (condensin). (Source: Haenng C.H. 2002. Mot- Cd! 9:773 - 776,1-6, page 785.)
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