In preparation for cell duplication via the cyclical process termed mitosis, cellular DNA content is doubled (see Figure 1). During one phase of the mitotic cycle termed metaphase, the duplicated chromosomes condense and can readily be visualized. Condensed chromosomes possess a twofold symmetry, with the identical duplicated sister chromatids connected at a chromosomal structure termed the centromere, the relative position of which is characteristic for a given chromosome (Figure 2). The centromere is an adenine–thymine (A–T)-rich region containing repeated DNA sequences that range in size from 10² (brewers’ yeast) to 10⁶ (mammals) base pairs (bp). Metazoan centromeres are bound by nucleosomes containing the special histone H3 variant protein CENP-A and other specific centromere-binding proteins. This complex, called the kinetochore, provides the anchor for the mitotic spindle, on which chromosomal segregation occurs during mitosis.

Fig1. Progress through the mammalian cell cycle is continuously monitored via multiple cell-cycle checkpoints. DNA, chromosome, and chromosome segregation integrity are continuously monitored throughout the cell cycle. If DNA damage is detected in either the G1 or the G2 phase of the cell cycle, if the genome is incompletely replicated, or if normal chromosome segregation machinery is incomplete (ie, a defective spindle), cells will not progress through the phase of the cycle in which defects are detected. In some cases, if the damage cannot be repaired, such cells undergo programmed cell death (apoptosis). Note that cells can reversibly leave the cell cycle during G1 entering a nonreplicative state termedG0. When appropriate signals/conditions occur, cells reenter G1 and progress normally through the cell cycle as depicted.

Fig2. The two sister chromatids of mitotic human chromosome 12.The dashed line demarcates the sister chromatids. The location of the A+T-rich centromeric region connecting sister chromatids is indicated, as are two of the four telomeres residing at the very ends of the chromatids that are attached one to the other at the centromere. (Reproduced with permission from Biophoto Associates/Photo Researchers, Inc.)

The ends of each chromosome contain structures called telomeres. Telomeres consist of short TG-rich repeats. Human telomeres have a variable number of repeats of the sequence 5′-TTAGGG-3′, which can extend for several kilobases. Telomerase, a multisubunit RNA template-containing complex related to viral RNA-dependent DNA polymerases (reverse transcriptases), is the enzyme responsible for telomere synthesis, and thus for maintaining the length of the telomere. Since telomere shortening has been associated with both malignant transformation  and aging, this enzyme has become an attractive target for cancer chemo therapy and drug development. Each sister chromatid contains one dsDNA molecule. As schematized in Figure 3, during interphase, the packing of the DNA molecule is less dense than it is in the condensed chromosome during metaphase. Metaphase chromosomes are nearly completely transcriptionally inactive.

Fig3. Extent of DNA packaging in metaphase chromosomes (top) to noted duplex DNA (bottom). Chromosomal DNA is packaged and organized at several levels as shown. Each phase of condensation or compaction and organization (bottom to top) decreases overall DNA accessibility to an extent that the DNA sequences in metaphase chromosomes are likely almost totally transcription ally inert. In toto, these five levels of DNA compaction result in nearly a 10⁴-fold linear decrease in end-to-end DNA length. Complete condensation and decondensation of the linear DNA in chromosomes occur in the space of just a few hours during the normal replicative cell cycle (see Figure 1).

The human haploid genome consists of about 3 × 10⁹bp and about 1.7 × 10⁷ nucleosomes. Thus, each of the 23 chromatids in the human haploid genome would contain on the average 1.3 × 10⁸ nucleotides in one dsDNA molecule. Consequently, the length of each DNA molecule must be compressed about 8000-fold to generate the structure of a condensed metaphase chromosome. In metaphase chromosomes, the 30-nm chromatin fibers are also folded into a series of looped domains, the proximal portions of which are anchored to the nuclear matrix, likely through interactions with proteins termed lam ins that constitute integral components of the inner nuclear membrane within the nucleus (see Figures 3). The packing ratios of each of the orders of DNA structure are summarized in Table 1. Though chromosomes are highly compacted, certain transcription proteins have been shown to still be able to access their target DNA sequences. The pack aging of nucleoproteins within chromatids is not random, as evidenced by the characteristic patterns observed when chromosomes are stained with specific dyes such as quinacrine or Giemsa stain (Figure 4).

Table1. The Packing or Compaction Ratios of Each of the Orders of DNA Structure

Fig4. A human karyotype (of a man with a normal 46,XY constitution), in which the metaphase chromosomes have been stained by the Giemsa method and aligned according to the Paris Convention. (Reproduced with permission from H Lawce and F Conte.)

From individual to individual within a single species, the pattern of staining (banding) of the entire chromosome complement is highly reproducible; nonetheless, it differs significantly between species, even those closely related. Thus, the packaging of the nucleoproteins in chromosomes of higher eukaryotes must in some way be dependent on species-specific characteristics of the DNA molecules.

A combination of specialized staining techniques and high-resolution microscopy has allowed cytogeneticists to quite precisely map many genes to specific regions of mouse and human chromosomes. With the recent elucidation of the human and mouse genome sequences (among others), it has become clear that many of these visual mapping methods were remarkably accurate.

Coding Regions Are Often Interrupted by Intervening Sequences

The protein coding regions of DNA, the transcripts of which ultimately appear in the cytoplasm as single mRNA molecules, are usually interrupted in the eukaryotic genome by large intervening sequences of nonprotein-coding DNA. Accordingly, the primary transcripts or mRNA precursors (originally termed hnRNA because this species of RNA was quite heterogeneous in size [length] and mostly restricted to the nucleus), contain nonprotein coding intervening sequences of RNA that must be removed in a process that also joins together the appropriate protein-coding segments to form the mature mRNA. Most coding sequences for a single mRNA are interrupted in the genome (and thus in the primary transcript) by at least one—and in some cases as many as 50—noncoding intervening sequences termed introns. In most cases, the introns are much longer than the coding regions termed exons. The processing of the primary transcript, which involves precise removal of introns and splicing of adjacent exons.

The function of the intervening sequences, or introns, is not totally clear. However, mRNA precursor molecules can be differentially spliced thereby increasing the number of dis tinct (yet related) proteins produced by a single gene and its corresponding primary mRNA gene transcript. Introns may also serve to separate functional domains (exons) of coding information in a form that permits genetic rearrangement by recombination to occur more rapidly than if all coding regions for a given genetic function were contiguous. Such an enhanced rate of genetic rearrangement of functional domains might allow more rapid evolution of biologic function. In some instances, other protein-coding or noncoding RNAs are localized within the intronic DNA of certain genes. The relationships among chromosomal DNA, gene clusters on the chromosome, the exon–intron structure of genes, and the final mRNA product are illustrated in Figure 5.

Fig5. The relationship between chromosomal DNA and mRNA. The human haploid DNA complement of 3 × 109bp is unequally distributed between 23 chromosomes (see Figure 4). Genes are often clustered on these chromosomes. An average gene is 2 × 10⁴ bp in length, including the regulatory region (red-hatched area), which is often located at the 5’ end of the gene. The regulatory region is shown here as being adjacent to the transcription initiation site (bent arrow). Most eukaryotic genes have alternating exons and introns. In this example, there are nine exons (blue-colored areas) and eight introns (green-colored areas). The introns are removed from the primary transcript by processing reactions, and the exons are ligated together in sequence to form the mature mRNA through a process termed RNA splicing. (nt, nucleotides.)

اخر الاخبار

اخبار العتبة العباسية المقدسة

مستشفى الكفيل يدخل قائمة الاعتماد الدولية بجودة الخدمة وسلامة المرضى

جامعة العميد تقيم ورشة عمل تدريبية في مجال التعليم الطبي الحديث

سماحة السيد الصافي يدعو إلى الاستمرار في تحقيق تراث العلماء الأعلام وتسليط الضوء على فكرهم

شعبة الخطابة الحسينية تختتم الموسم الثامن من مشروع الدورات الصيفية في كربلاء

المزيد

الآخبار الصحية

الأطعمة الحارة.. "سر صغير" يغير صحة قلبك وعقلك

وباء صامت.. الملايين حول العالم مصابون بالسكري دون أن يعلموا !

لماذا ينصح بتناول تفاحة يوميا؟

8 فواكه طبيعية تمنحك نوما هنيئا.. وتخلصك من الأرق

المزيد

الآخبار التكنلوجية

ثلاث علامات على وجود مشاكل خطيرة في محرك السيارة ؟

ماذا نعرف عن اللقاح الروسي ضد السرطان؟

مركبة فضاء تعثر على دليل عن وجود حياة قديمة على المريخ

لتدريب الذكاء الاصطناعي.. الصين تخطط لإنشاء شبكة حوسبة موحدة

المزيد

مواضيع ذات صلة

The Exact Function of Much of the Mammalian Genome is Not Well Understood

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology

The ras-fos-jun Pathway

Recessive Oncogenic Mutations, Tumor Suppressors

Small RNA

Ribosomal RNA

Messenger RNA

Identification of the src and sis Gene