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eukaryotic genomes.docx

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Laura Parker

Eukaryotic Genomes: Organization, Regulation, and Evolution I. Chromatin structure is based on successive levels of DNA packing. A. Eukaryotic DNA is precisely combined with large amounts of protein. B. Eukaryotic chromosomes contain an enormous amount of DNA relative to th8ir condensed length. Each human chromosome averages about 1.5 × 10 nucleotide pairs. If extended, each DNA molecule would be about 4 cm long, thousands of times longer than the cell diameter. C. The chromosomes fit into the nucleus through an elaborate, multilevel system of DNA packing. D. Histone proteins are responsible for the first level of DNA packaging. 1. The mass of histone in chromatin is approximately equal to the mass of DNA. 2. Their positively charged amino acids bind tightly to negatively charged DNA. 3. The five types of histones are very similar from one eukaryote to another, and similar proteins are found in prokaryotes. 4. The conservation of histone genes during evolution reflects their pivotal role in organizing DNA within cells. 5. Unfolded chromatin has the appearance of beads on a string. a. In this configuration, a chromatin fiber is 10 nm in diameter (the 10-nm fiber). b. Each bead of chromatin is a nucleosome, the basic unit of DNA packing. c. The ―string‖ between the beads is called linker DNA. 6. A nucleosome consists of DNA wound around a protein core composed of two molecules each of four types of histone: H2A, H2B, H3, and H4. a. A molecule of a fifth histone, H1, attaches to the DNA near the nucleosome. 7. The beaded string seems to remain essentially intact throughout the cell cycle. 8. Histones leave the DNA only transiently during DNA replication and they stay with the DNA during transcription. a. By changing shape and position, nucleosomes allow RNA- synthesizing polymerases to move along the DNA. E. The next level of packing is due to the interactions between the histone tails of one nucleosome and the linker DNA and nucleosomes to either side. 1. With the aid of histone H1, these interactions cause the 10-nm to coil to form the 30-nm chromatin fiber. 2. This fiber forms looped domains attached to a scaffold of nonhistone proteins to make up a 300-nm fiber. 3. In a mitotic chromosome, the looped domains coil and fold to produce the characteristic metaphase chromosome. 4. An interphase chromosome lacks an obvious scaffold, but its looped domains seem to be attached to the nuclear lamina on the inside of the nuclear envelope, and perhaps also to fibers of the nuclear matrix. 5. The chromatin of each chromosome occupies a specific restricted area within the interphase nucleus. 6. Interphase chromosomes have highly condensed areas, heterochromatin, and less compacted areas, euchromatin. a. Heterochromatin DNA is largely inaccessible to transcription enzymes presumably because they cannot reach the DNA . b. Looser packing of euchromatin makes its DNA accessible to enzymes and available for transcription. II. In addition to its role in packing DNA inside the nucleus, chromatin organization regulates gene expression. A. Histone acetylation (addition of an acetyl group —COCH ) and d3acetylation appear to play a direct role in the regulation of gene transcription. 1. Acetylated histones grip DNA less tightly, providing easier access for transcription proteins in this region. 2. Some of the enzymes responsible for acetylation or deacetylation are associated with or are components of transcription factors that bind to promoters. 3. Thus histone acetylation enzymes may promote the initiation of transcription not only by modifying chromatin structure, but also by binding to and recruiting components of the transcription machinery. B. DNA methylation is the attachment by specific enzymes of methyl groups (— CH )3to DNA bases after DNA synthesis. 1. Inactive DNA is generally highly methylated compared to DNA that is actively transcribed. 2. DNA methylation proteins recruit histone deacetylation enzymes, providing a mechanism by which DNA methylation and histone deacetylation cooperate to repress transcription. 3. Once methylated, genes usually stay that way through successive cell divisions. 4. Methylation enzymes recognize sites on one strand that are already methylated and correctly methylate the daughter strand after each round of DNA replication. 5. This methylation patterns accounts for genomic imprinting in which methylation turns off either the maternal or paternal alleles of certain genes at the start of development. a. The chromatin modifications just discussed do not alter DNA sequence, and yet they may be passed along to future generations of cells. b. Inheritance of traits by mechanisms not directly involving the nucleotide sequence is called epigenetic inheritance. III. Transcription initiation is controlled by proteins that interact with DNA and with each other. A. Chromatin-modifying enzymes provide initial control of gene expression by making a region of DNA either more available or less available for transcription. B. A cluster of proteins called a transcription initiation complex assembles on the promoter sequence at the ―upstream‖ end of the gene. C. One component, RNA polymerase II, transcribes the gene, synthesizing a primary RNA transcript or pre-mRNA. D. Multiple control elements are associated with most eukaryotic genes. 1. Control elements are noncoding DNA segments that regulate transcription by binding certain proteins. 2. These control elements and the proteins they bind are critical to the precise regulation of gene expression in different cell types. E. To initiate transcription, eukaryotic RNA polymerase requires the assistance of proteins called transcription factors. 1. Only a few general transcription factors independently bind a DNA sequence such as the TATA box within the promoter. 2. Others in the initiation complex are involved in protein-protein interactions, binding each other and RNA polymerase II. 3. The interaction of general transcription factors and RNA polymerase II with a promoter usually leads to only a low rate of initiation and production of few RNA transcripts. 4. In eukaryotes, high levels of transcription of particular genes depend on the interaction of control elements with specific transcription factors. 5. Some control elements, named proximal control elements, are located close to the promoter. 6. Distant control elements, enhancers, may be thousands of nucleotides away from the promoter or even downstream of the gene or within an intron. a. A given gene may have multiple enhancers, each active at a different time or in a different cell type or location in the organism. b. An activator is a protein that binds to an enhancer to stimulate transcription of a gene. 7. Protein-mediated bending of DNA brings bound activators in contact with a group of mediator proteins that interact with proteins at the promoter. This helps assemble and position the initiation complex on the promoter. 8. Eukaryotic genes also have repressor proteins to inhibit expression of a gene. a. Eukaryotic repressors can cause inhibition of gene expression by blocking the binding of activators to their control elements or to components of the transcription machinery or by turning off transcription even in the presence of activators. 9. Some activators and repressors act indirectly to influence chromatin structure. a. Some activators recruit proteins that acetylate histones near the promoters of specific genes, promoting transcription. b. Some repressors recruit proteins that deacetylate histones, reducing transcription or silencing the gene. c. Recruitment of chromatin-modifying proteins seems to be the most common mechanism of repression in eukaryotes. 10. For many genes, the particular combination of control elements associated with the gene may be more important than the presence of a single unique control element in regulating transcription of the gene. Even with only a dozen control element sequences, a large number of combinations are possible. a. A particular combination of control elements will be able to activate transcription only when the appropriate activator proteins are present, such as at a precise time during development or in a particular cell type. b. The use of different combinations of control elements allows fine regulation of transcription with a small set of control elements. 11. Remember that in prokaryotes, coordinately controlled genes are often clustered into an operon with a single promoter and other control elements upstream. The genes of the operon are transcribed into a single mRNA and translated together. 12. In contrast, very few eukaryotic genes are organized this way. Some coexpressed genes are clustered near each other on the same chromosome. a. Each eukaryotic gene in these clusters has its own promoter and is individually transcribed. b. The coordinate regulation of clustered genes in eukaryotic cells is thought to involve changes in the chromatin structure that makes the entire group of genes either available or unavailable for transcription. c. More commonly, genes coding for the enzymes of a metabolic pathway are scattered over different chromosomes. d. Coordinate gene expression in eukaryotes depends on the association of a specific control element or combination of control elements with every gene of a dispersed group. e. A common group of transcription factors binds to all the genes in the group, promoting simultaneous gene transcription. IV. Post-transcriptional mechanisms play supporting roles in the control of gene expression. A. By using regulatory mechanisms that operate after transcription, a cell can rapidly fine-tune gene expression in response to environmental changes without altering its transcriptional patterns. B. RNA processing in the nucleus and the export of mRNA to the cytoplasm provide opportunities for gene regulation that are not available in bacteria. C. In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments are treated as exons and which as introns. 1. Regulatory proteins specific to a cell type control intron-exon choices by binding to regulatory sequences within the primary transcript. D. The life span of an mRNA molecule is an important factor in determining the pattern of protein synthesis. 1. Prokaryotic mRNA molecules may be degraded after only a few minutes. 2. Eukaryotic mRNAs typically last for hours, days, or weeks. 3. A common pathway of mRNA breakdown begins with enzymatic shortening of the poly-A tail. a. This triggers the enzymatic removal of the 5’ cap. b. This is followed by rapid degradation of the mRNA by nucleases. 4. During the past few years, researchers have found small single-stranded RNA molecules called microRNAs, or miRNAs, that bind to complementary sequences in mRNA molecules. a. miRNAs are formed from longer RNA precursors that fold back on themselves, forming a long hairpin structure stabilized by hydrogen bonding. b. An enzyme called Dicer cuts the double-stranded RNA into short fragments. c. One of the two strands is degraded. The other miRNA strand associates with a protein complex and directs the complex to any mRNA molecules with a complementary sequence. d. The miRNA-protein complex then degrades the target mRNA or blocks its translation. e. The phenomenon of inhibition of gene expression by RNA molecules is called RNA interference (RNAi). f. Small interfering RNAs (siRNAs) are similar in size and function to miRNAs and are generated by similar mechanisms in eukaryotic cells. g. Cellular RNAi pathways lead to the destruction of RNAs and may have originated as a natural defense against infection by RNA viruses. E. Translation of specific mRNAs can be blocked by regulatory proteins that bind to specific sequences or structures within the 5’ leader region of mRNA. This prevents attachment of ribosomes. F. mRNAs may be stored in egg cells without poly-A tails of sufficient size to allow translation initiation. 1. At the appropriate time during development, a cytoplasmic enzyme adds more A residues, allowing translation to begin. G. Protein factors required to initiate translation in eukaryotes offer targets for simultaneously controlling translation of all mRNAs in a cell. 1. This allows the cell to shut down translation if environmental conditions are poor (for example, shortage of a key constituent) or until the appropriate conditions exist (for example, after fertilization in an egg or during daylight in plants). V. Cancer results from genetic changes that affect the cell cycle. A. Cancer is a disease in which cells escape the control methods that normally regulate cell growth and division. B. The gene regulation systems that go wrong during cancer are the very same
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