Fundamental molecular biology /
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ISBN：9781405103794
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简介
Summary:
Publisher Summary 1
Featuring full color illustrations throughout, this introductory textbook uses an accessible style to teach students the essential concepts of molecular biology. Allison (biology, College of William and Mary) employs mainly eukaryotic examples, but comparisons with prokaryotic organisms are made where appropriate. The CD-ROM contains downloadable artwork from the text as well as a sample interactive animation and tutorial. Annotation 漏2007 Book News, Inc., Portland, OR (booknews.com)
Publisher Summary 2
The author received the 2009 Outstanding Faculty Award, the Commonwealth of Virginia's highest honor for faculty, in January 2009.More accessible to beginning students in the field than its encyclopedic counterparts, Fundamental Molecular Biologyprovides a distillation of the essential concepts of molecular biology, and is supported by current examples, experimental evidence, an outstanding art program, multimedia support and a solid pedagogical framework. The text has been praised both for its balanced and solid coverage of traditional topics, and for its broad coverage of RNA structure and function, epigenetics and medical molecular biology.Focuses primarily on eukaryotic examples but includes key comparisons with prokaryotic organisms where it is appropriateIncludes all-original artwork providing the clearest possible insight into complex concepts. All artwork is available online and on CD-ROMSupplemented by outstanding student and instructor media resources including a CD-ROM that comes with every book and an interactive website at www.blackwellpublishing.com/allison featuring all artwork, animations of key processes, and useful student comprehension materialPedagogical boxes throughout explain additional concepts and topics in molecular biology:
-TOOLS BOXESexplore key experimental methods and techniques in molecular biology
-FOCUS BOXESoffer more detailed treatment of topics and delve into experimental strategies, historical background and areas for further exploration
-DISEASE BOXESillustrate key principles of molecular biology by examining diseases that result from gene defectsVisit www.blackwellpublishing.com/allison to access helpful student and instructor resources online.Note:CD-ROM/DVD and other supplementary materials are not included as part of eBook file.
目录
Table Of Contents:
Preface xviii
The beginnings of molecular biology 1(12)
Introduction
Historical perspective
Insights into heredity from round and wrinkled peas: Mendelian genetics
Insights into the nature of hereditary material: the transforming principle is DNA
Creativity in approach leads to the one gene--one enzyme hypothesis
The importance of technological advances: the Hershey--Chase experiment
A model for the structure of DNA: the DNA double helix
Chapter summary
Analytical questions
Suggestions for further reading
The structure of DNA 13(24)
Introduction
Primary structure: the components of nucleic acids
Five-carbon sugars
Nitrogenous bases
The phosphate functional group
Nucleosides and nucleotides
Significance of 5' and 3'
Nomenclature of nucleotides
The length of RNA and DNA
Secondary structure of DNA
Hydrogen bonds form between the bases
Base stacking provides chemical stability to the DNA double helix
Structure of the Watson--Crick DNA double helix
Distinguishing between features of alternative double-helical structures
DNA can undergo reversible strand separation
Unusual DNA secondary structures
Slipped structures
Cruciform structures
Triple helix DNA
Disease box 2.1 Friedreich's ataxia and triple helix DNA
Tertiary structure of DNA
Supercoiling of DNA
Topoisomerases relax supercoiled DNA
What is the significance of supercoiling in vivo?
Disease box 2.2 Topoisomerase-targeted anticancer drugs
Chapter summary
Analytical questions
Suggestions for further reading
Genome organization: from nucleotides to chromatin 37(17)
Introduction
Eukaryotic genome
Chromatin structure: historical perspective
Histones
Nucleosomes
Beads-on-a-string: the 10 nm fiber
The 30 nm fiber
Loop domains
Metaphase chromosomes
Alternative chromatin structures
Bacterial genome
Plasmids
Bacteriophages and mammalian DNA viruses
Bacteriophages
Mammalian DNA viruses
Organelle genomes: chloroplasts and mitochondria
Chloroplast DNA (cpDNA)
Mitochondrial DNA (mtDNA)
Disease box 3.1 Mitochondrial DNA and disease
RNA-based genomes
Eukaryotic RNA viruses
Retroviruses
Viroids
Other subviral pathogens
Disease box 3.2 Avian flu
Chapter summary
Analytical questions
Suggestions for further reading
The versatility of RNA 54(25)
Introduction
Secondary structure of RNA
Secondary structure motifs in RNA
Base-paired RNA adopts an A-type double helix
RNA helices often contain noncanonical base pairs
Tertiary structure of RNA
tRNA structure: important insights into RNA structural motifs
Common tertiary structure motifs in RNA
Kinetics of RNA folding
RNA is involved in a wide range of cellular processes
Historical perspective: the discovery of RNA catalysis
Tetrahymena group I intron ribozyme
RNase P ribozyme
Focus box 4.1: The RNA world
Ribozymes catalyze a variety of chemical reactions
Mode of ribozyme action
Large ribozymes
Small ribozymes
Chapter summary
Analytical questions
Suggestions for further reading
From gene to protein 79(29)
Introduction
The central dogma
The genetic code
Translating the genetic code
The 21st and 22nd genetically encoded amino acids
Role of modified nucleotides in decoding
Implications of codon bias for molecular biologists
Protein structure
Primary structure
Secondary structure
Tertiary structure
Quaternary structure
Size and complexity of proteins
Proteins contain multiple functional domains
Prediction of protein structure
Protein function
Enzymes are biological catalysts
Regulation of protein activity by post-translational modifications
Allosteric regulation of protein activity
Cyclin-dependent kinase activation
Macromolecular assemblages
Protein folding and misfolding
Molecular chaperones
Ubiquitin-mediated protein degradation
Protein misfolding diseases
Disease box 5.1 Prions
Chapter summary
Analytical questions
Suggestions for further reading
DNA replication and telomere maintenance 108(44)
Introduction
Historical perspective
Insight into the mode of DNA replication: the Meselson--Stahl experiment
Insight into the mode of DNA replication: visualization of replicating bacterial DNA
DNA synthesis occurs from 5' → 3'
DNA polymerases are the enzymes that catalyze DNA synthesis
Focus box 6.1 Bacterial DNA polymerases
Semidiscontinuous DNA replication
Leading strand synthesis is continuous
Lagging strand synthesis is discontinuous
Nuclear DNA replication in eukaryotic cells
Replication factories
Histone removal at the origins of replication
Prereplication complex formation at the origins of replication
Replication licensing: DNA only replicates once per cell cycle
Duplex unwinding at replication forks
RNA priming of leading strand and lagging strand DNA synthesis
Polymerase switching
Elongation of leading strands and lagging strands
Proofreading
Maturation of nascent DNA strands
Termination
Histone deposition
Focus box 6.2 The naming of genes involved in DNA replication
Disease box 6.1 Systemic lupus erythematosus and PCNA
Replication of organelle DNA
Models for mtDNA replication
Replication of cpDNA
Disease box 6.2 RNase MRP and cartilage-hair hypoplasia
Rolling circle replication
Telomere maintenance: the role of telomerase in DNA replication, aging, and cancer
Telomeres
Solution to the end replication problem
Maintenance of telomeres by telomerase
Other modes of telomere maintenance
Regulation of telomerase activity
Telomerase, aging, and cancer
Disease box 6.3 Dyskeratosis congenita: loss of telomerase function
Chapter summary
Analytical questions
Suggestions for further reading
DNA repair and recombination 152(28)
Introduction
Types of mutations and their phenotypic consequences
Transitions and transversions can lead to silent, missense, or nonsense mutations
Insertions or deletions can cause frameshift mutations
Expansion of trinucleotide repeats leads to genetic instability
General classes of DNA damage
Single base changes
Structural distortion
DNA backbone damage
Cellular response to DNA damage
Lesion bypass
Direct reversal of DNA damage
Repair of single base changes and structural distortions by removal of DNA damage
Base excision repair
Mismatch repair
Nucleotide excision repair
Disease box 7.1 Hereditary nonpolyposis colorectal cancer: a defect in mismatch repair
Double-strand break repair by removal of DNA damage
Homologous recombination
Nonhomologous end-joining
Disease box 7.2 Xeroderma pigmentosum and related disorders: defects in nucleotide excision repair
Disease box 7.3 Hereditary breast cancer syndromes: mutations in BRCA1 and BRCA2
Chapter summary
Analytical questions
Suggestions for further reading
Recombinant DNA technology and molecular cloning 180(52)
Introduction
Historical perspective
Insights from bacteriophage lambda (λ) cohesive sites
Insights from bacterial restriction and modification systems
The first cloning experiments
Cutting and joining DNA
Major classes of restriction endonucleases
Restriction endonuclease nomenclature
Recognition sequences for type II restriction endonucleases
DNA ligase
Focus box 8.1 Fear of recombinant DNA molecules
Molecular cloning
Vector DNA
Choice of vector is dependent on insert size and application
Plasmid DNA as a vector
Bacteriophage lambda [λ] as a vector
Artificial chromosome vectors
Sources of DNA for cloning
Focus box 8.2 EcoRI: kinking and cutting DNA
Tool box 8.1 Liquid chromatography
Constructing DNA libraries
Genomic library
cDNA library
Probes
Heterologous probes
Homologous probes
Tool box 8.2 Complementary DNA (cDNA) synthesis
Tool box 8.3 Polymerase chain reaction (PCR)
Tool box 8.4 Radioactive and nonradioactive labeling methods
Tool box 8.5 Nucleic acid labeling
Library screening
Transfer of colonies to a DNA-binding membrane
Colony hybridization
Detection of positive colonies
Expression libraries
Restriction mapping
Restriction fragment length polymorphism (RFLP)
RFLPs can serve as markers of genetic diseases
Tool box 8.6 Electrophoresis
Tool box 8.7 Southern blot
Disease box 8.1 PCR-RFLP assay for maple syrup urine disease
DNA sequencing
Manual DNA sequencing by the Sanger ``dideoxy'' DNA method
Automated DNA sequencing
Chapter summary
Analytical questions
Suggestions for further reading
Tools for analyzing gene expression 232(46)
Introduction
Transient and stable transfection assays
Reporter genes
Commonly used reporter genes
Analysis of gene regulation
Purification and detection tags: fusion proteins
Tool box 9.1 Production of recombinant proteins
In vitro mutagenesis
Tool box 9.2 Fluorescence, confocal, and multiphoton microscopy
Analysis at the level of gene transcription: RNA expression and localization
Northern blot
In situ hybridization
RNase protection assay (RPA)
Reverse transcription-PCR (RT-PCR)
Analysis at the level of translation: protein expression and localization
Western blot
In situ analysis
Enzyme-linked immunosorbent assay (ELISA)
Tool box 9.3 Protein gel electrophoresis
Tool box 9.4 Antibody production
Antisense technology
Antisense oligonucleotides
RNA interference (RNAi)
Analysis of DNA-protein interactions
Electrophoretic mobility shift assay (EMSA)
DNase I footprinting
Chromatin immunoprecipitation (ChIP) assay
Disease box 9.1 RNAi therapies
Analysis of protein--protein interactions
Pull-down assay
Yeast two-hybrid assay
Coimmunoprecipitation assay
Fluorescence resonance energy transfer (FRET)
Structural analysis of proteins
X-ray crystallography
Nuclear magnetic resonance (NMR) spectroscopy
Cryoelectron microscopy
Atomic force microscopy (AFM)
Model organisms
Yeast: Saccharomyces cerevisiae and Schizosaccharomyces pombe
Worm: Caenorhabditis elegans
Fly: Drosophila melanogaster
Fish: Danio rerio
Plant: Arabidopsis thaliana
Mouse: Mus musculus
Frog: Xenopus laevis and Xenopus tropicalis
Chapter summary
Analytical questions
Suggestions for further reading
Transcription in prokaryotes 278(34)
Introduction
Transcription and translation are coupled in bacteria
Mechanism of transcription
Bacterial promoter structure
Structure of bacterial RNA polymerase
Stages of transcription
Proofreading
Direction of transcription around the E. coli chromosome
Focus box 10.1 Which moves
the RNA polymerase or the DNA?
Historical perspective: the Jacob--Monod operon model of gene regulation
The operon model led to the discovery of mRNA
Characterization of the Lac repressor
Lactose [lac] operon regulation
Lac operon induction
Basal transcription of the lac operon
Regulation of the lac operon by Rho
The lac promoter and lacZ structural gene are widely used in molecular biology research
Mode of action of transcriptional regulators
Cooperative binding of proteins to DNA
Allosteric modifications and DNA binding
DNA looping
Control of gene expression by RNA
Differential folding of RNA: transcriptional attenuation of the tryptophan operon
Riboswitches
Riboswitch ribozymes
Chapter summary
Analytical questions
Suggestions for further reading
Transcription in eukaryotes 312(80)
Introduction
Overview of transcriptional regulation
Protein-coding gene regulatory elements
Structure and function of promoter elements
Structure and function of long-range regulatory elements
Focus box 11.1 Position effect and long-range regulatory elements
Disease box 11.1 Hispanic thalassemia and DNase I hypersensitive sites
Focus box 11.2 Is there a nuclear matrix?
Focus box 11.3 Chromosomal territories and transcription factories
General (basal) transcription machinery
Components of the general transcription machinery
Structure of RNA polymerase II
General transcription factors and preinitiation complex formation
Mediator: a molecular bridge
Transcription factors
Transcription factors mediate gene-specific transcriptional activation or repression
Transcription factors are modular proteins
DNA-binding domain motifs
Transactivation domain
Dimerization domain
Focus box 11.4 Homeoboxes and homeodomains
Disease box 11.2 Greig cephalopolysyndactyly syndrome and Sonic hedgehog signaling
Disease box 11.3 Defective histone acetyltransferases in Rubinstein-Taybi syndrome
Transcriptional coactivators and corepressors
Chromatin modification complexes
Linker histone variants
Chromatin remodeling complexes
Focus box 11.5 Is there a histone code?
Transcription complex assembly: the enhanceosome model versus the ``hit and run'' model
Order of recruitment of various proteins that regulate transcription
Enhanceosome model
Hit and run model
Merging of models
Mechanism of RNA polymerase II transcription
Promoter clearance
Elongation: polymerization of RNA
Proofreading and backtracking
Transcription elongation through the nucleosomal barrier
Disease box 11.4 Defects in Elongator and familial dysautonomia
Nuclear import and export of proteins
Karyopherins
Nuclear localization sequences (NLSs)
Nuclear export sequences (NESs)
Nuclear import pathway
Nuclear export pathway
Focus box 11.6 The nuclear pore complex
Focus box 11.7 Characterization of the first nuclear localization sequence
Regulated nuclear import and signal transduction pathways
Regulated nuclear import of NF-κB
Regulated nuclear import of the glucocorticoid receptor
Chapter summary
Analytical questions
Suggestions for further reading
Epigenetics and monoallelic gene expression 392(60)
Introduction
Epigenetic markers
Cytosine DNA methylation marks genes for silencing
Stable maintenance of histone modifications
Disease box 12.1 Cancer and epigenetics
Genomic imprinting
Establishing and maintaining the imprint
Mechanisms of monoallelic expression
Genomic imprinting is essential for normal development
Origins of genomic imprinting
Disease box 12.2 Fragile X mental retardation and aberrant DNA methylation
Disease box 12.3 Genomic imprinting and neurodevelopmental disorders
X chromosome inactivation
Random X chromosome inactivation in mammals
Molecular mechanisms for stable maintenance of X chromosome inactivation
Is there monoallelic expression of all X-linked genes?
Phenotypic consequences of transposable elements
Historical perspective: Barbara McClintock's discovery of mobile genetic elements in maize
DNA transposons have a wide host range
DNA transposons move by a ``cut and paste'' mechanism
Retrotransposons move by a ``copy and paste'' mechanism
Some LTR retrotransposons are active in the mammalian genome
Non-LTR retrotransposons include LINEs and SINEs
Tool box 12.1 Transposon tagging
Disease box 12.4 Jumping genes and human disease
Epigenetic control of transposable elements
Methylation of transposable elements
Heterochromatin formation mediated by RNAi and RNA-directed DNA methylation
Allelic exclusion
Yeast mating-type switching and silencing
Antigen switching in trypanosomes
V(D)J recombination and the adaptive immune response
Disease box 12.5 Trypanosomiasis: human ``sleeping sickness''
Focus box 12.1 Did the V(D)J system evolve from a transposon?
Chapter summary
Analytical questions
Suggestions for further reading
RNA processing and post-transcriptional gene regulation 452(60)
Introduction
RNA splicing: historical perspective and overview
Group I and group II self-splicing introns
Group I introns require an external G cofactor for splicing
Group II introns require an internal bulged A for splicing
Mobile group I and II introns
Focus box 13.1 Intron-encoded small nucleolar RNA and ``inside-out'' genes
Archael and nuclear transfer RNA introns
Archael introns are spliced by an endoribonuclease
Some nuclear tRNA genes contain an intron
Cotranscriptional processing of nuclear pre-mRNA
Addition of the 5'-7-methylguanosine cap
Termination and polyadenylation
Splicing
Disease box 13.1 Oculopharyngeal muscular dystrophy: trinucleotide repeat expansion in a poly(A)-binding protein gene
Disease box 13.2 Spinal muscular atrophy: defects in snRNP biogenesis
Disease box 13.3 Prp8 gene mutations cause retinitis pigmentosa
Alternative splicing
Effects of alternative splicing on gene expression
Regulation of alternative splicing
Focus box 13.2 The DSCAM gene: extreme alternative splicing
Trans-splicing
Discontinuous group II trans-splicing
Spliced leader trans-splicing
tRNA trans-splicing
Focus box 13.3 Apoptosis
RNA editing
RNA editing in trypanosomes
RNA editing in mammals
Disease box 13.4 Amyotrophic lateral sclerosis: a defect in RNA editing?
Base modification guided by small nucleolar RNA molecules
Post-transcriptional gene regulation by microRNA
Historical perspective: the discovery of miRNA in Caenorhabditis elegans
Processing of miRNAs
miRNAs target mRNA for degradation and translational inhibition
RNA turnover in the nucleus and cytoplasm
Nuclear exosomes and quality control
Quality control and the formation of nuclear export-competent RNPs
Cytoplasmic RNA turnover
Chapter summary
Analytical questions
Suggestions for further reading
The mechanism of translation 512(33)
Introduction
Ribosome structure and assembly
Structure of ribosomes
The nucleolus
Ribosome biogenesis
Focus box 14.1 What is ``S''?
Aminoacyl-tRNA synthetases
Aminoacyl-tRNA charging
Proofreading activity of aminoacyl-tRNA synthetases
Initiation of translation
Ternary complex formation and loading onto the 40S ribosomal subunit
Loading the mRNA on the 40S ribosomal subunit
Scanning and AUG recognition
Joining of the 40S and 60S ribosomal subunits
Tool box 14.1 Translation toeprinting assays
Disease box 14.1 Eukaryotic initiation factor 2B and vanishing white matter
Elongation
Decoding
Peptide bond formation and translocation
Peptidyl transferase activity
Events in the ribosome tunnel
Termination
Translational and post-translational control
Phosphorylation of elF2α blocks ternary complex formation
elF2α phosphorylation is mediated by four distinct protein kinases
Chapter summary
Analytical questions
Suggestions for further reading
Genetically modified organisms: use in basic and applied research 545(36)
Introduction
Transgenic mice
How to make a transgenic mouse
Inducible transgenic mice
Focus box 15.1 Oncomouse patent
Gene-targeted mouse models
Knockout mice
Knockin mice
Knockdown mice
Conditional knockout and knockin mice
Focus box 15.2 A mouse for every need
Other applications of transgenic animal technology
Transgenic primates
Transgenic livestock
Gene pharming
Focus box 15.3 Transgenic artwork: the GFP bunny
Cloning by nuclear transfer
Genetic equivalence of somatic cell nuclei: frog cloning experiments
Cloning of mammals by nuclear transfer
``Breakthrough of the year'': the cloning of Dolly
Method for cloning by nuclear transfer
Source of mtDNA in clones
Why is cloning by nuclear transfer inefficient?
Applications of cloning by nuclear transfer
Focus box 15.4 Genetically manipulated pets
Transgenic plants
T-DNA-mediated gene delivery
Electroporation and microballistics
Focus box 15.5 Genetically modified crops: are you eating genetically engineered tomatoes?
Chapter summary
Analytical questions
Suggestions for further reading
Genome analysis: DNA typing, genomics, and beyond 581(37)
Introduction
DNA typing
DNA polymorphisms: the basis of DNA typing
Minisatellite analysis
Polymerase chain reaction-based analysis
Short tandem repeat analysis
Mitochondrial DNA analysis
Y chromosome analysis
Randomly amplified polymorphic DNA (RAPD) analysis
Focus box 16.1 DNA profiles of marijuana
Focus box 16.2 Nonhuman DNA typing
Genomics and beyond
What is bioinformatics?
Genomics
Proteomics
The age of ``omics''
The Human Genome Project
Clone by clone genome assembly approach
Whole-genome shotgun approach
Rough drafts versus finished sequences
Other sequenced genomes
What is a gene and how many are there in the human genome?
Focus box 16.3 Comparative analysis of genomes: insights from pufferfish and chickens
High-throughput analysis of gene function
DNA microarrays
Protein arrays
Mass spectrometry
Single nucleotide polymorphisms
Focus box 16.4 The nucleolar proteome
Disease box 16.1 Mapping disease-associated SNPs: Alzheimer's disease
Chapter summary
Analytical questions
Suggestions for further reading
Medical molecular biology 618(50)
Introduction
Molecular biology of cancer
Activation of oncogenes
Inactivation of tumor suppressor genes
Inappropriate expression of microRNAs in cancer
Chromosomal rearrangements and cancer
Viruses and cancer
Chemical carcinogenesis
Focus box 17.1 How cancer cells metastasize: the role of Src
Disease box 17.1 Knudson's two-hit hypothesis and retinoblastoma
Disease box 17.2 Cancer gene therapy: a ``magic bullet?''
Focus box 17.2 The discovery of p53
Disease box 17.3 Human papilioma virus (HPV) and cervical cancer
Gene therapy
Vectors for somatic cell gene therapy
Enhancement genetic engineering
Gene therapy for inherited immunodeficiency syndromes
Cystic fibrosis gene therapy
HIV-1 gene therapy
Focus box 17.3 Retroviral-mediated gene transfer: how to make a ``safe vector''
Focus box 17.4 The first gene therapy fatality
Focus box 17.5 HIV-1 life cycle
Genes and human behavior
Aggressive, impulsive, and violent behavior
Schizophrenia susceptibility loci
Chapter summary
Analytical questions
Suggestions for further reading
Glossary 668(43)
Index 711
Preface xviii
The beginnings of molecular biology 1(12)
Introduction
Historical perspective
Insights into heredity from round and wrinkled peas: Mendelian genetics
Insights into the nature of hereditary material: the transforming principle is DNA
Creativity in approach leads to the one gene--one enzyme hypothesis
The importance of technological advances: the Hershey--Chase experiment
A model for the structure of DNA: the DNA double helix
Chapter summary
Analytical questions
Suggestions for further reading
The structure of DNA 13(24)
Introduction
Primary structure: the components of nucleic acids
Five-carbon sugars
Nitrogenous bases
The phosphate functional group
Nucleosides and nucleotides
Significance of 5' and 3'
Nomenclature of nucleotides
The length of RNA and DNA
Secondary structure of DNA
Hydrogen bonds form between the bases
Base stacking provides chemical stability to the DNA double helix
Structure of the Watson--Crick DNA double helix
Distinguishing between features of alternative double-helical structures
DNA can undergo reversible strand separation
Unusual DNA secondary structures
Slipped structures
Cruciform structures
Triple helix DNA
Disease box 2.1 Friedreich's ataxia and triple helix DNA
Tertiary structure of DNA
Supercoiling of DNA
Topoisomerases relax supercoiled DNA
What is the significance of supercoiling in vivo?
Disease box 2.2 Topoisomerase-targeted anticancer drugs
Chapter summary
Analytical questions
Suggestions for further reading
Genome organization: from nucleotides to chromatin 37(17)
Introduction
Eukaryotic genome
Chromatin structure: historical perspective
Histones
Nucleosomes
Beads-on-a-string: the 10 nm fiber
The 30 nm fiber
Loop domains
Metaphase chromosomes
Alternative chromatin structures
Bacterial genome
Plasmids
Bacteriophages and mammalian DNA viruses
Bacteriophages
Mammalian DNA viruses
Organelle genomes: chloroplasts and mitochondria
Chloroplast DNA (cpDNA)
Mitochondrial DNA (mtDNA)
Disease box 3.1 Mitochondrial DNA and disease
RNA-based genomes
Eukaryotic RNA viruses
Retroviruses
Viroids
Other subviral pathogens
Disease box 3.2 Avian flu
Chapter summary
Analytical questions
Suggestions for further reading
The versatility of RNA 54(25)
Introduction
Secondary structure of RNA
Secondary structure motifs in RNA
Base-paired RNA adopts an A-type double helix
RNA helices often contain noncanonical base pairs
Tertiary structure of RNA
tRNA structure: important insights into RNA structural motifs
Common tertiary structure motifs in RNA
Kinetics of RNA folding
RNA is involved in a wide range of cellular processes
Historical perspective: the discovery of RNA catalysis
Tetrahymena group I intron ribozyme
RNase P ribozyme
Focus box 4.1: The RNA world
Ribozymes catalyze a variety of chemical reactions
Mode of ribozyme action
Large ribozymes
Small ribozymes
Chapter summary
Analytical questions
Suggestions for further reading
From gene to protein 79(29)
Introduction
The central dogma
The genetic code
Translating the genetic code
The 21st and 22nd genetically encoded amino acids
Role of modified nucleotides in decoding
Implications of codon bias for molecular biologists
Protein structure
Primary structure
Secondary structure
Tertiary structure
Quaternary structure
Size and complexity of proteins
Proteins contain multiple functional domains
Prediction of protein structure
Protein function
Enzymes are biological catalysts
Regulation of protein activity by post-translational modifications
Allosteric regulation of protein activity
Cyclin-dependent kinase activation
Macromolecular assemblages
Protein folding and misfolding
Molecular chaperones
Ubiquitin-mediated protein degradation
Protein misfolding diseases
Disease box 5.1 Prions
Chapter summary
Analytical questions
Suggestions for further reading
DNA replication and telomere maintenance 108(44)
Introduction
Historical perspective
Insight into the mode of DNA replication: the Meselson--Stahl experiment
Insight into the mode of DNA replication: visualization of replicating bacterial DNA
DNA synthesis occurs from 5' → 3'
DNA polymerases are the enzymes that catalyze DNA synthesis
Focus box 6.1 Bacterial DNA polymerases
Semidiscontinuous DNA replication
Leading strand synthesis is continuous
Lagging strand synthesis is discontinuous
Nuclear DNA replication in eukaryotic cells
Replication factories
Histone removal at the origins of replication
Prereplication complex formation at the origins of replication
Replication licensing: DNA only replicates once per cell cycle
Duplex unwinding at replication forks
RNA priming of leading strand and lagging strand DNA synthesis
Polymerase switching
Elongation of leading strands and lagging strands
Proofreading
Maturation of nascent DNA strands
Termination
Histone deposition
Focus box 6.2 The naming of genes involved in DNA replication
Disease box 6.1 Systemic lupus erythematosus and PCNA
Replication of organelle DNA
Models for mtDNA replication
Replication of cpDNA
Disease box 6.2 RNase MRP and cartilage-hair hypoplasia
Rolling circle replication
Telomere maintenance: the role of telomerase in DNA replication, aging, and cancer
Telomeres
Solution to the end replication problem
Maintenance of telomeres by telomerase
Other modes of telomere maintenance
Regulation of telomerase activity
Telomerase, aging, and cancer
Disease box 6.3 Dyskeratosis congenita: loss of telomerase function
Chapter summary
Analytical questions
Suggestions for further reading
DNA repair and recombination 152(28)
Introduction
Types of mutations and their phenotypic consequences
Transitions and transversions can lead to silent, missense, or nonsense mutations
Insertions or deletions can cause frameshift mutations
Expansion of trinucleotide repeats leads to genetic instability
General classes of DNA damage
Single base changes
Structural distortion
DNA backbone damage
Cellular response to DNA damage
Lesion bypass
Direct reversal of DNA damage
Repair of single base changes and structural distortions by removal of DNA damage
Base excision repair
Mismatch repair
Nucleotide excision repair
Disease box 7.1 Hereditary nonpolyposis colorectal cancer: a defect in mismatch repair
Double-strand break repair by removal of DNA damage
Homologous recombination
Nonhomologous end-joining
Disease box 7.2 Xeroderma pigmentosum and related disorders: defects in nucleotide excision repair
Disease box 7.3 Hereditary breast cancer syndromes: mutations in BRCA1 and BRCA2
Chapter summary
Analytical questions
Suggestions for further reading
Recombinant DNA technology and molecular cloning 180(52)
Introduction
Historical perspective
Insights from bacteriophage lambda (λ) cohesive sites
Insights from bacterial restriction and modification systems
The first cloning experiments
Cutting and joining DNA
Major classes of restriction endonucleases
Restriction endonuclease nomenclature
Recognition sequences for type II restriction endonucleases
DNA ligase
Focus box 8.1 Fear of recombinant DNA molecules
Molecular cloning
Vector DNA
Choice of vector is dependent on insert size and application
Plasmid DNA as a vector
Bacteriophage lambda [λ] as a vector
Artificial chromosome vectors
Sources of DNA for cloning
Focus box 8.2 EcoRI: kinking and cutting DNA
Tool box 8.1 Liquid chromatography
Constructing DNA libraries
Genomic library
cDNA library
Probes
Heterologous probes
Homologous probes
Tool box 8.2 Complementary DNA (cDNA) synthesis
Tool box 8.3 Polymerase chain reaction (PCR)
Tool box 8.4 Radioactive and nonradioactive labeling methods
Tool box 8.5 Nucleic acid labeling
Library screening
Transfer of colonies to a DNA-binding membrane
Colony hybridization
Detection of positive colonies
Expression libraries
Restriction mapping
Restriction fragment length polymorphism (RFLP)
RFLPs can serve as markers of genetic diseases
Tool box 8.6 Electrophoresis
Tool box 8.7 Southern blot
Disease box 8.1 PCR-RFLP assay for maple syrup urine disease
DNA sequencing
Manual DNA sequencing by the Sanger ``dideoxy'' DNA method
Automated DNA sequencing
Chapter summary
Analytical questions
Suggestions for further reading
Tools for analyzing gene expression 232(46)
Introduction
Transient and stable transfection assays
Reporter genes
Commonly used reporter genes
Analysis of gene regulation
Purification and detection tags: fusion proteins
Tool box 9.1 Production of recombinant proteins
In vitro mutagenesis
Tool box 9.2 Fluorescence, confocal, and multiphoton microscopy
Analysis at the level of gene transcription: RNA expression and localization
Northern blot
In situ hybridization
RNase protection assay (RPA)
Reverse transcription-PCR (RT-PCR)
Analysis at the level of translation: protein expression and localization
Western blot
In situ analysis
Enzyme-linked immunosorbent assay (ELISA)
Tool box 9.3 Protein gel electrophoresis
Tool box 9.4 Antibody production
Antisense technology
Antisense oligonucleotides
RNA interference (RNAi)
Analysis of DNA-protein interactions
Electrophoretic mobility shift assay (EMSA)
DNase I footprinting
Chromatin immunoprecipitation (ChIP) assay
Disease box 9.1 RNAi therapies
Analysis of protein--protein interactions
Pull-down assay
Yeast two-hybrid assay
Coimmunoprecipitation assay
Fluorescence resonance energy transfer (FRET)
Structural analysis of proteins
X-ray crystallography
Nuclear magnetic resonance (NMR) spectroscopy
Cryoelectron microscopy
Atomic force microscopy (AFM)
Model organisms
Yeast: Saccharomyces cerevisiae and Schizosaccharomyces pombe
Worm: Caenorhabditis elegans
Fly: Drosophila melanogaster
Fish: Danio rerio
Plant: Arabidopsis thaliana
Mouse: Mus musculus
Frog: Xenopus laevis and Xenopus tropicalis
Chapter summary
Analytical questions
Suggestions for further reading
Transcription in prokaryotes 278(34)
Introduction
Transcription and translation are coupled in bacteria
Mechanism of transcription
Bacterial promoter structure
Structure of bacterial RNA polymerase
Stages of transcription
Proofreading
Direction of transcription around the E. coli chromosome
Focus box 10.1 Which moves
the RNA polymerase or the DNA?
Historical perspective: the Jacob--Monod operon model of gene regulation
The operon model led to the discovery of mRNA
Characterization of the Lac repressor
Lactose [lac] operon regulation
Lac operon induction
Basal transcription of the lac operon
Regulation of the lac operon by Rho
The lac promoter and lacZ structural gene are widely used in molecular biology research
Mode of action of transcriptional regulators
Cooperative binding of proteins to DNA
Allosteric modifications and DNA binding
DNA looping
Control of gene expression by RNA
Differential folding of RNA: transcriptional attenuation of the tryptophan operon
Riboswitches
Riboswitch ribozymes
Chapter summary
Analytical questions
Suggestions for further reading
Transcription in eukaryotes 312(80)
Introduction
Overview of transcriptional regulation
Protein-coding gene regulatory elements
Structure and function of promoter elements
Structure and function of long-range regulatory elements
Focus box 11.1 Position effect and long-range regulatory elements
Disease box 11.1 Hispanic thalassemia and DNase I hypersensitive sites
Focus box 11.2 Is there a nuclear matrix?
Focus box 11.3 Chromosomal territories and transcription factories
General (basal) transcription machinery
Components of the general transcription machinery
Structure of RNA polymerase II
General transcription factors and preinitiation complex formation
Mediator: a molecular bridge
Transcription factors
Transcription factors mediate gene-specific transcriptional activation or repression
Transcription factors are modular proteins
DNA-binding domain motifs
Transactivation domain
Dimerization domain
Focus box 11.4 Homeoboxes and homeodomains
Disease box 11.2 Greig cephalopolysyndactyly syndrome and Sonic hedgehog signaling
Disease box 11.3 Defective histone acetyltransferases in Rubinstein-Taybi syndrome
Transcriptional coactivators and corepressors
Chromatin modification complexes
Linker histone variants
Chromatin remodeling complexes
Focus box 11.5 Is there a histone code?
Transcription complex assembly: the enhanceosome model versus the ``hit and run'' model
Order of recruitment of various proteins that regulate transcription
Enhanceosome model
Hit and run model
Merging of models
Mechanism of RNA polymerase II transcription
Promoter clearance
Elongation: polymerization of RNA
Proofreading and backtracking
Transcription elongation through the nucleosomal barrier
Disease box 11.4 Defects in Elongator and familial dysautonomia
Nuclear import and export of proteins
Karyopherins
Nuclear localization sequences (NLSs)
Nuclear export sequences (NESs)
Nuclear import pathway
Nuclear export pathway
Focus box 11.6 The nuclear pore complex
Focus box 11.7 Characterization of the first nuclear localization sequence
Regulated nuclear import and signal transduction pathways
Regulated nuclear import of NF-κB
Regulated nuclear import of the glucocorticoid receptor
Chapter summary
Analytical questions
Suggestions for further reading
Epigenetics and monoallelic gene expression 392(60)
Introduction
Epigenetic markers
Cytosine DNA methylation marks genes for silencing
Stable maintenance of histone modifications
Disease box 12.1 Cancer and epigenetics
Genomic imprinting
Establishing and maintaining the imprint
Mechanisms of monoallelic expression
Genomic imprinting is essential for normal development
Origins of genomic imprinting
Disease box 12.2 Fragile X mental retardation and aberrant DNA methylation
Disease box 12.3 Genomic imprinting and neurodevelopmental disorders
X chromosome inactivation
Random X chromosome inactivation in mammals
Molecular mechanisms for stable maintenance of X chromosome inactivation
Is there monoallelic expression of all X-linked genes?
Phenotypic consequences of transposable elements
Historical perspective: Barbara McClintock's discovery of mobile genetic elements in maize
DNA transposons have a wide host range
DNA transposons move by a ``cut and paste'' mechanism
Retrotransposons move by a ``copy and paste'' mechanism
Some LTR retrotransposons are active in the mammalian genome
Non-LTR retrotransposons include LINEs and SINEs
Tool box 12.1 Transposon tagging
Disease box 12.4 Jumping genes and human disease
Epigenetic control of transposable elements
Methylation of transposable elements
Heterochromatin formation mediated by RNAi and RNA-directed DNA methylation
Allelic exclusion
Yeast mating-type switching and silencing
Antigen switching in trypanosomes
V(D)J recombination and the adaptive immune response
Disease box 12.5 Trypanosomiasis: human ``sleeping sickness''
Focus box 12.1 Did the V(D)J system evolve from a transposon?
Chapter summary
Analytical questions
Suggestions for further reading
RNA processing and post-transcriptional gene regulation 452(60)
Introduction
RNA splicing: historical perspective and overview
Group I and group II self-splicing introns
Group I introns require an external G cofactor for splicing
Group II introns require an internal bulged A for splicing
Mobile group I and II introns
Focus box 13.1 Intron-encoded small nucleolar RNA and ``inside-out'' genes
Archael and nuclear transfer RNA introns
Archael introns are spliced by an endoribonuclease
Some nuclear tRNA genes contain an intron
Cotranscriptional processing of nuclear pre-mRNA
Addition of the 5'-7-methylguanosine cap
Termination and polyadenylation
Splicing
Disease box 13.1 Oculopharyngeal muscular dystrophy: trinucleotide repeat expansion in a poly(A)-binding protein gene
Disease box 13.2 Spinal muscular atrophy: defects in snRNP biogenesis
Disease box 13.3 Prp8 gene mutations cause retinitis pigmentosa
Alternative splicing
Effects of alternative splicing on gene expression
Regulation of alternative splicing
Focus box 13.2 The DSCAM gene: extreme alternative splicing
Trans-splicing
Discontinuous group II trans-splicing
Spliced leader trans-splicing
tRNA trans-splicing
Focus box 13.3 Apoptosis
RNA editing
RNA editing in trypanosomes
RNA editing in mammals
Disease box 13.4 Amyotrophic lateral sclerosis: a defect in RNA editing?
Base modification guided by small nucleolar RNA molecules
Post-transcriptional gene regulation by microRNA
Historical perspective: the discovery of miRNA in Caenorhabditis elegans
Processing of miRNAs
miRNAs target mRNA for degradation and translational inhibition
RNA turnover in the nucleus and cytoplasm
Nuclear exosomes and quality control
Quality control and the formation of nuclear export-competent RNPs
Cytoplasmic RNA turnover
Chapter summary
Analytical questions
Suggestions for further reading
The mechanism of translation 512(33)
Introduction
Ribosome structure and assembly
Structure of ribosomes
The nucleolus
Ribosome biogenesis
Focus box 14.1 What is ``S''?
Aminoacyl-tRNA synthetases
Aminoacyl-tRNA charging
Proofreading activity of aminoacyl-tRNA synthetases
Initiation of translation
Ternary complex formation and loading onto the 40S ribosomal subunit
Loading the mRNA on the 40S ribosomal subunit
Scanning and AUG recognition
Joining of the 40S and 60S ribosomal subunits
Tool box 14.1 Translation toeprinting assays
Disease box 14.1 Eukaryotic initiation factor 2B and vanishing white matter
Elongation
Decoding
Peptide bond formation and translocation
Peptidyl transferase activity
Events in the ribosome tunnel
Termination
Translational and post-translational control
Phosphorylation of elF2α blocks ternary complex formation
elF2α phosphorylation is mediated by four distinct protein kinases
Chapter summary
Analytical questions
Suggestions for further reading
Genetically modified organisms: use in basic and applied research 545(36)
Introduction
Transgenic mice
How to make a transgenic mouse
Inducible transgenic mice
Focus box 15.1 Oncomouse patent
Gene-targeted mouse models
Knockout mice
Knockin mice
Knockdown mice
Conditional knockout and knockin mice
Focus box 15.2 A mouse for every need
Other applications of transgenic animal technology
Transgenic primates
Transgenic livestock
Gene pharming
Focus box 15.3 Transgenic artwork: the GFP bunny
Cloning by nuclear transfer
Genetic equivalence of somatic cell nuclei: frog cloning experiments
Cloning of mammals by nuclear transfer
``Breakthrough of the year'': the cloning of Dolly
Method for cloning by nuclear transfer
Source of mtDNA in clones
Why is cloning by nuclear transfer inefficient?
Applications of cloning by nuclear transfer
Focus box 15.4 Genetically manipulated pets
Transgenic plants
T-DNA-mediated gene delivery
Electroporation and microballistics
Focus box 15.5 Genetically modified crops: are you eating genetically engineered tomatoes?
Chapter summary
Analytical questions
Suggestions for further reading
Genome analysis: DNA typing, genomics, and beyond 581(37)
Introduction
DNA typing
DNA polymorphisms: the basis of DNA typing
Minisatellite analysis
Polymerase chain reaction-based analysis
Short tandem repeat analysis
Mitochondrial DNA analysis
Y chromosome analysis
Randomly amplified polymorphic DNA (RAPD) analysis
Focus box 16.1 DNA profiles of marijuana
Focus box 16.2 Nonhuman DNA typing
Genomics and beyond
What is bioinformatics?
Genomics
Proteomics
The age of ``omics''
The Human Genome Project
Clone by clone genome assembly approach
Whole-genome shotgun approach
Rough drafts versus finished sequences
Other sequenced genomes
What is a gene and how many are there in the human genome?
Focus box 16.3 Comparative analysis of genomes: insights from pufferfish and chickens
High-throughput analysis of gene function
DNA microarrays
Protein arrays
Mass spectrometry
Single nucleotide polymorphisms
Focus box 16.4 The nucleolar proteome
Disease box 16.1 Mapping disease-associated SNPs: Alzheimer's disease
Chapter summary
Analytical questions
Suggestions for further reading
Medical molecular biology 618(50)
Introduction
Molecular biology of cancer
Activation of oncogenes
Inactivation of tumor suppressor genes
Inappropriate expression of microRNAs in cancer
Chromosomal rearrangements and cancer
Viruses and cancer
Chemical carcinogenesis
Focus box 17.1 How cancer cells metastasize: the role of Src
Disease box 17.1 Knudson's two-hit hypothesis and retinoblastoma
Disease box 17.2 Cancer gene therapy: a ``magic bullet?''
Focus box 17.2 The discovery of p53
Disease box 17.3 Human papilioma virus (HPV) and cervical cancer
Gene therapy
Vectors for somatic cell gene therapy
Enhancement genetic engineering
Gene therapy for inherited immunodeficiency syndromes
Cystic fibrosis gene therapy
HIV-1 gene therapy
Focus box 17.3 Retroviral-mediated gene transfer: how to make a ``safe vector''
Focus box 17.4 The first gene therapy fatality
Focus box 17.5 HIV-1 life cycle
Genes and human behavior
Aggressive, impulsive, and violent behavior
Schizophrenia susceptibility loci
Chapter summary
Analytical questions
Suggestions for further reading
Glossary 668(43)
Index 711
Fundamental molecular biology /
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