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Chapter 19 EUKARYOTIC GENOMES Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In eukaryotes, the DNA-protein complex, is called: – chromatin – Is ordered into higher structural levels than – The DNA-protein complex in prokaryotes Figure 19.1 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Chromatin structure is based on successive levels of DNA packing • Eukaryotic DNA – Is precisely combined with a large amount of protein • Eukaryotic chromosomes – Contain an enormous amount of DNA relative to their condensed length Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Nucleosomes, or “Beads on a String” • Proteins called histones: – Are responsible for the first level of DNA packing in chromatin – Bind tightly to DNA • The association of DNA and histones – Seems to remain intact throughout the cell cycle Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • In electron micrographs – Unfolded chromatin has the appearance of beads on a string • Each “bead” is a nucleosome, which is: – The basic unit of DNA packing 2 nm DNA double helix Histones Histone tails Histone H1 Linker DNA (“string”) Nucleosome (“bad”) (a) Nucleosomes (10-nm fiber) Figure 19.2 a Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings 10 nm Higher Levels of DNA Packing • The next level of packing – Forms the 30-nm chromatin fiber 30 nm Nucleosome (b) 30-nm fiber Figure 19.2 b Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • The 30-nm fiber, in turn – Forms looped domains, making up a 300-nm fiber Protein scaffold Loops 300 nm (c) Looped domains (300-nm fiber) Figure 19.2 c Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Scaffold • In a mitotic chromosome – The looped domains themselves coil and fold forming the characteristic metaphase chromosome 700 nm 1,400 nm (d) Metaphase chromosome Figure 19.2 d Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Gene expression can be regulated at any stage, but the key step is transcription • All organisms – Must regulate which genes are expressed at any given time • During development, cells of a multicellular organism undergo a process of: – specialization in form and function – This process is called cell differentiation Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Differential Gene Expression • Each cell of a multicellular eukaryote – Expresses only a fraction of its genes • In each type of differentiated cell – A unique subset of genes is expressed Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Regulation of Chromatin Structure Interphase chromatin can exist in two forms: – heterochromatin: “highly condensed form”. – euchromatin: “less compacted form” • Genes within highly packed heterochromatin – Are usually not expressed Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Histone Modification • Chemical modification of histone tails – Can affect the configuration of chromatin and thus gene expression Chromatin changes Transcription RNA processing mRNA degradation Translation Protein processing and degradation Histone tails DNA double helix Amino acids available for chemical modification Figure 19.4a (a) Histone tails protrude outward from a nucleosome Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Histone acetylation & deacetylation • Acetylation loosens chromatin structure, and – Enhances transcription • Deacetylation condenses chromatin structure, and – Suppresses transcription. Unacetylated histones Figure 19.4 b Acetylated histones (b) Acetylation of histone tails promotes loose chromatin structure that permits transcription Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings DNA Methylation & Epigenetic Inheritance • DNA methylation: – Methyl groups addition to certain DNA bases – Associated with reduced transcription in some species • Epigenetic inheritance – The inheritance of traits transmitted by mechanisms not directly involving the nucleotide sequence: – Example: Inheritance of methylation Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Regulation of Transcription Initiation • Carried by chromatin modifying enzymes • They provide initial control of gene expression by: – making a region of DNA either more or less able to bind the transcription machinery Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Organization of a Typical Eukaryotic Gene • multiple control elements are associated with most eukaryotic genes: – Segments of noncoding DNA that help regulate transcription by binding certain proteins Enhancer (distal control elements) Poly-A signal Termination sequence region Proximal control elements Exon Intron Exon Intron Exon DNA Downstream Upstream Promoter Chromatin changes Transcription Exon Primary RNA 5 transcript (pre-mRNA) Intron Exon RNA processing: Cap and tail added; introns excised and exons spliced together Transcription Intron RNA RNA processing mRNA degradation Cleared 3 end of primary transport Coding segment Translation Protein processing and degradation Poly-A signal Intron Exon mRNA G P Figure 19.5 Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings P P 5 Cap 5 UTR (untranslated region) Start codon Stop codon Poly-A 3 UTR (untranslated tail region) The Roles of Transcription Factors • To initiate transcription – Eukaryotic RNA polymerase requires the assistance of proteins called: • transcription factors Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Enhancers and Specific Transcription Factors • Proximal control elements – Are located close to the promoter • Distal control elements, groups of which are called enhancers – May be far away from a gene or even in an intron Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Some specific transcription factors function as repressors – To inhibit expression of a particular gene • Some activators and repressors – Act indirectly by influencing chromatin structure Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Protein Processing and Degradation • After translation – Various types of protein processing, including: • Cleavage of chemical groups • addition of chemical groups, are subject to control Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Cancer • Cancer results from: – genetic changes that affect cell cycle control • The gene regulation systems that go wrong during cancer are: – the very same systems that play important roles in: • embryonic development Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Types of Genes Associated with Cancer • The genes that normally regulate cell growth and division during the cell cycle Include: – genes for: • Growth factors, • Growth factors receptors, and • Intracellular signaling pathways molecules Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Oncogenes and Proto-Oncogenes • Oncogenes – Are cancer-causing genes • Proto oncogenes – Are normal cellular genes that – code for proteins that stimulate: • normal cell growth and division Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Tumor-Suppressor Genes • Tumor suppressor genes – Encode proteins that inhibit abnormal cell division Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Interference with Normal Cell-Signaling Pathways • Many proto oncogenes and tumor suppressor genes, respectively, encode components of: – growth-stimulating pathways – growth-inhibiting pathways Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Multistep Model of Cancer Development • Normal cells are converted to cancer cells – By the accumulation of: • multiple mutations affecting: – proto-oncogenes and – tumor-suppressor genes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Certain viruses – Promote cancer by integration of viral DNA into a cell’s genome Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings Inherited Predisposition to Cancer • Individuals who inherit a mutant oncogene or tumor suppressor allele – Have an increased risk of developing certain types of cancer Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings • Eukaryotic genomes can have many noncoding DNA sequences in addition to genes • The bulk of most eukaryotic genomes – Consists of noncoding DNA sequences, often described in the past as: • “junk DNA” • However, much evidence is accumulating – That noncoding DNA plays important roles in the cell Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings The Relationship Between Genomic Composition and Organismal Complexity • Compared with prokaryotic genomes, the genomes of eukaryotes – Generally are larger – Have longer genes – Contain a much greater amount of noncoding DNA both associated: • with genes and • between genes Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings