Table of contents for Genes VIII / Benjamin Lewin.


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Contents
Part 1 Genes
1 Genes are DNA
	1.1 	Introduction	1	
	1.2	DNA is the genetic material of bacteria 	3
	1.3 	DNA is the genetic material of viruses	3
	1.4 	DNA is the genetic material of animal cells 	4
	1.5 	Polynucleotide chains have nitrogenous bases linked to a 
sugar-phosphate backbone 	5
	1.6 	DNA is a double helix 	6
	1.7 	DNA replication is semiconservative 	7
	1.8 	DNA strands separate at the replication fork 	8
	1.9 	Nucleic acids hybridize by base pairing 	9
	1.10 	Mutations change the sequence of DNA 	10
	1.11 	Mutations may affect single base pairs or longer sequences 	11
	1.12 	The effects of mutations can be reversed 	13
	1.13 	Mutations are concentrated at hotspots 	13
	1.14 	Many hotspots result from modified bases 	14
	1.15 	A gene codes for a single polypeptide 	15
	1.16 	Mutations in the same gene cannot complement 	16
	1.17 	Mutations may cause loss-of-function or gain-of-function 	18
	1.18 	A locus may have many different mutant alleles 	18
	1.19 	A locus may have more than one wild-type allele 	19
	1.20 	Recombination occurs by physical exchange of DNA 	20
	1.21 	The genetic code is triplet 	21
	1.22 	Every sequence has three possible reading frames 	23
	1.23 	Prokaryotic genes are colinear with their proteins 	24
	1.24 	Several processes are required to express the protein product of a gene 
	25
	1.25 	Proteins are trans-acting but sites on DNA are cis-acting 	26
	1.26	Genetic information can be provided by DNA or RNA 	27
	1.27	Some hereditary agents are extremely small 	29
	1.28	Summary 	30
2 The interrupted gene
	2.1 	Introduction 	33	
	2.2 	An interrupted gene consists of exons and introns 	34	
	2.3 	Restriction endonucleases are a key tool in mapping DNA 	35	
	2.4 	Organization of interrupted genes may be conserved 	36	
	2.5 	Exon sequences are conserved but introns vary 	37	
	2.6	Genes can be isolated by the conservation of exons 	38	
	2.7	Genes show a wide distribution of sizes 	40	
	2.8	Some DNA sequences code for more than one protein 	41	
	2.9 	How did interrupted genes evolve? 	43	
	2.10 	Some exons can be equated with protein functions 	45	
	2.11 	The members of a gene family have a common organization 	46	
	2.12 	Is all genetic information contained in DNA? 	48	
	2.13 	Summary 	49
3 The content of the genome
	3.1 	Introduction 	51
	3.2 	Genomes can be mapped by linkage, restriction cleavage, or DNA sequence 
	52
	3.3 	Individual genomes show extensive variation 	53	
	3.4 	RFLPs and SNPs can be used for genetic mapping 	54	
	3.5 	Why are genomes so large? 	56	
	3.6	Eukaryotic genomes contain both nonrepetitive and repetitive DNA 
sequences 	57	
	3.7	Bacterial gene numbers range over an order of magnitude 	58	
	3.8	Total gene number is known for several eukaryotes 	60	
	3.9 	How many different types of genes are there? 	61	
	3.10 	The conservation of genome organization helps to identify genes 	63	
	3.11 	The human genome has fewer genes than expected 	65	
	3.12 	How are genes and other sequences distributed in the genome? 	67	
	3.13 	More complex species evolve by adding new gene functions 	68	
	3.14 	How many genes are essential? 	69	
	3.15 	Genes are expressed at widely differing levels 	72	
	3.16	How many genes are expressed? 	73	
	3.17	Expressed gene number can be measured en masse 	74	
	3.18	Organelles have DNA 	75	
	3.19 	Organelle genomes are circular DNAs that code for organelle proteins 
	76	
	3.20 	Mitochondrial DNA organization is variable 	77	
	3.21 	Mitochondria evolved by endosymbiosis 	78	
	3.22 	The chloroplast genome codes for many proteins and RNAs 	79	
	3.23 	Summary 	80
4 Clusters and repeats
	4.1 	Introduction 	85
	4.2	Gene duplication is a major force in evolution 	86
	4.3	Globin clusters are formed by duplication and divergence 	87
	4.4	Sequence divergence is the basis for the evolutionary clock 	89 
	4.5	The rate of neutral substitution can be measured from divergence of 
repeated sequences 	92
	4.6	Pseudogenes are dead ends of evolution 	93
	4.7	Unequal crossing-over rearranges gene clusters 	95
	4.8	Genes for rRNA form tandem repeats 	98
	4.9	The repeated genes for rRNA maintain constant sequence 	99
	4.10	Crossover fixation could maintain identical repeats 	100
	4.11	Satellite DNAs often lie in heterochromatin 	103
	4.12	Arthropod satellites have very short identical repeats 	105
	4.13	Mammalian satellites consist of hierarchical repeats 	106
	4.14	Minisatellites are useful for genetic mapping 	109
	4.15	Summary 	111
Part 2 Proteins
5 Messenger RNA
	5.1	Introduction 	113
	5.2	mRNA is produced by transcription and is translated 	114
	5.3	Transfer RNA forms a cloverleaf 	114
	5.4	The acceptor stem and anticodon are at ends of the tertiary structure 
	116
	5.5	Messenger RNA is translated by ribosomes 	117
	5.6	Many ribosomes bind to one mRNA 	118
	5.7	The life cycle of bacterial messenger RNA 	119
	5.8	Eukaryotic mRNA is modified during or after its transcription 	121
	5.9	The 5¢ end of eukaryotic mRNA is capped 	122
	5.10	The 3¢ terminus is polyadenylated 	123
	5.11	Bacterial mRNA degradation involves multiple enzymes 	124
	5.12	mRNA stability depends on its structure and sequence 	125
	5.13	mRNA degradation involves multiple activities 	126
	5.14	Nonsense mutations trigger a surveillance system 	127
	5.15	Eukaryotic RNAs are transported 	128
	5.16	mRNA can be specifically localized 	130
	5.17	Summary 	131
6 Protein synthesis
	6.1	Introduction 	135
	6.2	Protein synthesis occurs by initiation, elongation, and termination 
	136
	6.3	Special mechanisms control the accuracy of protein synthesis 	138
	6.4	Initiation in bacteria needs 30S subunits and accessory factors 	139
	6.5	A special initiator tRNA starts the polypeptide chain 	140
	6.6	Use of fMet-tRNAf is controlled by IF-2 and the ribosome 	141
	6.7	Initiation involves base pairing between mRNA and rRNA 	142
	6.8	Small subunits scan for initiation sites on eukaryotic mRNA 	144
	6.9	Eukaryotes use a complex of many initiation factors 	146
	6.10	Elongation factor Tu loads aminoacyl-tRNA into the A site 	148
	6.11	The polypeptide chain is transferred to aminoacyl-tRNA 	149
	6.12	Translocation moves the ribosome 	150
	6.13	Elongation factors bind alternately to the ribosome 	151
	6.14	Three codons terminate protein synthesis 	152
	6.15	Termination codons are recognized by protein factors 	153
	6.16	Ribosomal RNA pervades both ribosomal subunits 	155
	6.17	Ribosomes have several active centers 	157
	6.18	16S rRNA plays an active role in protein synthesis 	159
	6.19	23S rRNA has peptidyl transferase activity 	161
	6.20	Summary 	162
7 Using the genetic code
	7.1	Introduction 	167
	7.2	Codon-anticodon recognition involves wobbling 	169
	7.3	tRNAs are processed from longer precursors 	170
	7.4	tRNA contains modified bases 	171
	7.5	Modified bases affect anticodon-codon pairing 	173
	7.6	There are sporadic alterations of the universal code 	174
	7.7	Novel amino acids can be inserted at certain stop codons 	176
	7.8	tRNAs are charged with amino acids by synthetases 	177
	7.9	Aminoacyl-tRNA synthetases fall into two groups 	178
	7.10	Synthetases use proofreading to improve accuracy 	180
	7.11	Suppressor tRNAs have mutated anticodons that read new codons 	182
	7.12	There are nonsense suppressors for each termination codon 	183
	7.13	Suppressors may compete with wild-type reading of the code 	184
	7.14	The ribosome influences the accuracy of translation 	185
	7.15	Recoding changes codon meanings 	188
	7.16	Frameshifting occurs at slippery sequences 	189
	7.17	Bypassing involves ribosome movement 	190
	7.18	Summary 	191
8 Protein localization
	8.1	Introduction 	195
	8.2	Passage across a membrane requires a special apparatus 	196
	8.3	Protein translocation may be post-translational or co-translational 
	197
	8.4	Chaperones may be required for protein folding 	198
	8.5	Chaperones are needed by newly synthesized and by denatured proteins 
	199
	8.6	The Hsp70 family is ubiquitous 	201
	8.7	Hsp60/GroEL forms an oligomeric ring structure 	202
	8.8	Signal sequences initiate translocation 	203
	8.9	The signal sequence interacts with the SRP 	205
	8.10	The SRP interacts with the SRP receptor 	206
	8.11	The translocon forms a pore 	207
	8.12	Translocation requires insertion into the translocon and 
(sometimes) a ratchet in the ER 	209
	8.13	Reverse translocation sends proteins to the cytosol for degradation 
	210
	8.14	Proteins reside in membranes by means of hydrophobic regions 	211
	8.15	Anchor sequences determine protein orientation 	212
	8.16	How do proteins insert into membranes? 	213
	8.17	Post-translational membrane insertion depends on leader sequences 	214
	8.18	A hierarchy of sequences determines location within organelles 	215
	8.19	Inner and outer mitochondrial membranes have different translocons 
	217	
	8.20	Peroxisomes employ another type of translocation system 	219
	8.21	Bacteria use both co-translational and post-translational translocation 
	220
	8.22	The Sec system transports proteins into and through the inner membrane 
	221
	8.23	Sec-independent translation systems in E. coli 	222
	8.24	Pores are used for nuclear import and export 	223
	8.25	Nuclear pores are large symmetrical structures 	224
	8.26	The nuclear pore is a size-dependent sieve for smaller material 	225
	8.27	Proteins require signals to be transported through the pore 	226
	8.28	Transport receptors carry cargo proteins through the pore 	227
	8.29	Ran controls the direction of transport 	228
	8.30	RNA is exported by several systems 	230
	8.31	Ubiquitination targets proteins for degradation 	231
	8.32	The proteasome is a large machine that degrades ubiquitinated proteins 
	232
	8.33	Summary 	234
Part 3 Gene expression
9 Transcription
	9.1	Introduction 	241
	9.2	Transcription occurs by base pairing in a "bubble" of unpaired DNA 
	242
	9.3	The transcription reaction has three stages 	243
	9.4	Phage T7 RNA polymerase is a useful model system 	244
	9.5	A model for enzyme movement is suggested by the crystal structure 	245
	9.6	Bacterial RNA polymerase consists of multiple subunits 	246
	9.7	RNA polymerase consists of the core enzyme and sigma factor 	248
	9.8	The association with sigma factor changes at initiation 	249
	9.9	A stalled RNA polymerase can restart 	250
	9.10	How does RNA polymerase find promoter sequences? 	251
	9.11	Sigma factor controls binding to DNA 	252
	9.12	Promoter recognition depends on consensus sequences 	253
	9.13	Promoter efficiencies can be increased or decreased by mutation 	255
	9.14	RNA polymerase binds to one face of DNA 	256
	9.15	Supercoiling is an important feature of transcription 	258
	9.16	Substitution of sigma factors may control initiation 	259
	9.17	Sigma factors directly contact DNA 	261
	9.18	Sigma factors may be organized into cascades 	263
	9.19	Sporulation is controlled by sigma factors 	264
	9.20	Bacterial RNA polymerase terminates at discrete sites 	266
	9.21	There are two types of terminators in E. coli 	267
	9.22	How does rho factor work? 	268
	9.23	Antitermination is a regulatory event 	270
	9.24	Antitermination requires sites that are independent of the terminators 
	271
	9.25	Termination and anti-termination factors interact with RNA polymerase 
	272
	9.26	Summary 	274
10 The operon
	10.1	Introduction 	279
	10.2	Regulation can be negative or positive 	280
	10.3	Structural gene clusters are coordinately controlled 	281
	10.4	The lac genes are controlled by a repressor 	282
	10.5	The lac operon can be induced 	283
	10.6	Repressor is controlled by a small molecule inducer 	284
	10.7	cis-acting constitutive mutations identify the operator 	286
	10.8	trans-acting mutations identify the regulator gene 	287
	10.9	Multimeric proteins have special genetic properties 	288
	10.10	Repressor protein binds to the operator 	288
	10.11	Binding of inducer releases repressor from the operator 	289
	10.12	The repressor monomer has several domains 	290
	10.13	Repressor is a tetramer made of two dimers 	291
	10.14	DNA-binding is regulated by an allosteric change in conformation 	291
	10.15	Mutant phenotypes correlate with the domain structure 	292
	10.16	Repressor binds to three operators and interacts with RNA polymerase 
	293
	10.17	Repressor is always bound to DNA 	294
	10.18	The operator competes with low-affinity sites to bind repressor 	295
	10.19	Repression can occur at multiple loci 	297
	10.20	Summary 	298
11 Regulatory circuits
	11.1	Introduction 	301
	11.2	Distinguishing positive and negative control 	302
	11.3	Glucose repression controls use of carbon sources 	304
	11.4	Cyclic AMP is an inducer that activates CRP to act at many operons 
	305
	11.5	CRP functions in different ways in different target operons 	305
	11.6	CRP bends DNA 	307
	11.7	The stringent response produces (p)ppGpp 	308
	11.8	(p)ppGpp is produced by the ribosome 	309
	11.9	ppGpp has many effects 	310
	11.10	Translation can be regulated 	311
	11.11	r-protein synthesis is controlled by autogenous regulation 	312
	11.12	Phage T4 p32 is controlled by an autogenous circuit 	313
	11.13	Autogenous regulation is often used to control synthesis of 
macromolecular assemblies 
	314
	11.14	Alternative secondary structures control attenuation 	315
	11.15	Termination of B. subtilis trp genes is controlled by tryptophan 
and by tRNATrp 	316
	11.16	The E. coli tryptophan operon is controlled by attenuation 	316
	11.17	Attenuation can be controlled by translation 	318
	11.18	Antisense RNA can be used to inactivate gene expression 	319
	11.19	Small RNA molecules can regulate translation 	320
	11.20	Bacteria contain regulator RNAs 	321
	11.21	MicroRNAs are regulators in many eukaryotes 	322
	11.22	RNA interference is related to gene silencing 	323
	11.23	Summary 	325
12 Phage strategies
	12.1	Introduction 	329
	12.2	Lytic development is divided into two periods 	330
	12.3	Lytic development is controlled by a cascade 	331
	12.4	Two types of regulatory event control the lytic cascade 	332
	12.5	The T7 and T4 genomes show functional clustering 	333
	12.6	Lambda immediate early and delayed early genes are needed for 
both lysogeny and the lytic cycle 	334
	12.7	The lytic cycle depends on antitermination 	335
	12.8	Lysogeny is maintained by repressor protein 	336
	12.9	Repressor maintains an autogenous circuit 	337
	12.10	The repressor and its operators define the immunity region 	338
	12.11	The DNA-binding form of repressor is a dimer 	339
	12.12	Repressor uses a helix-turn-helix motif to bind DNA 	340
	12.13	The recognition helix determines specificity for DNA 	340
	12.14	Repressor dimers bind cooperatively to the operator 	342
	12.15	Repressor at OR2 interacts with RNA polymerase at PRM 	343
	12.16	The cII and cIII genes are needed to establish lysogeny 	344
	12.17	A poor promoter requires cII protein 	345
	12.18	Lysogeny requires several events 	346
	12.19	The cro repressor is needed for lytic infection 	347
	12.20	What determines the balance between lysogeny and the lytic cycle? 	349
	12.21	Summary 	350
Part 4 DNA
13 The replicon
	13.1	Introduction 	353
	13.2	Replicons can be linear or circular 	355
	13.3	Origins can be mapped by autoradiography and electrophoresis 	355
	13.4	The bacterial genome is a single circular replicon 	356
	13.5	Each eukaryotic chromosome contains many replicons 	358
	13.6	Replication origins can be isolated in yeast 	359
	13.7	D loops maintain mitochondrial origins 	361
	13.8	The ends of linear DNA are a problem for replication 	362
	13.9	Terminal proteins enable initiation at the ends of viral DNAs 	363
	13.10	Rolling circles produce multimers of a replicon 	364
	13.11	Rolling circles are used to replicate phage genomes 	364	
	13.12	The F plasmid is transferred by conjugation between bacteria 	366
	13.13	Conjugation transfers single-stranded DNA 	367
	13.14	Replication is connected to the cell cycle 	368
	13.15	The septum divides a bacterium into progeny each containing a chromosome 
	370
	13.16	Mutations in division or segregation affect cell shape 	371
	13.17	FtsZ is necessary for septum formation 	372
	13.18	min genes regulate the location of the septum 	373
	13.19	Chromosomal segregation may require site-specific recombination 	374
	13.20	Partitioning involves separation of the chromosomes 	375
	13.21	Single-copy plasmids have a partitioning system 	377
	13.22	Plasmid incompatibility is determined by the replicon 	379
	13.23	The ColE1 compatibility system is controlled by an RNA regulator 	380
	13.24	How do mitochondria replicate and segregate? 	382
	13.25	Summary 	383
14 DNA replication
	14.1	Introduction 	387
	14.2	DNA polymerases are the enzymes that make DNA 	388
	14.3	DNA polymerases have various nuclease activities 	389
	14.4	DNA polymerases control the fidelity of replication 	390
	14.5	DNA polymerases have a common structure 	391
	14.6	DNA synthesis is semidiscontinuous 	392
	14.7	The fX model system shows how single-stranded DNA is generated for 
replication 	393
	14.8	Priming is required to start DNA synthesis 	394
	14.9	Coordinating synthesis of the lagging and leading strands 	396
	14.10	DNA polymerase holoenzyme has 3 subcomplexes 	397
	14.11	The clamp controls association of core enzyme with DNA 	398
	14.12	Okazaki fragments are linked by ligase 	399
	14.13	Separate eukaryotic DNA polymerases undertake initiation and elongation 
	400
	14.14	Phage T4 provides its own replication apparatus 	402
	14.15	Creating the replication forks at an origin 	404
	14.16	Common events in priming replication at the origin 	405
	14.17	The primosome is needed to restart replication 	407
	14.18	Does methylation at the origin regulate initiation? 	408
	14.19	Origins may be sequestered after replication 	409
	14.20	Licensing factor controls eukaryotic rereplication 	411
	14.21	Licensing factor consists of MCM proteins 	412
	14.22	Summary 	413
15 Recombination and repair
	15.1	Introduction 	419
	15.2	Homologous recombination occurs between synapsed chromosomes 	420
	15.3	Breakage and reunion involves heteroduplex DNA 	422
	15.4	Double-strand breaks initiate recombination 	424
	15.5	Recombining chromosomes are connected by the synaptonemal complex 	425
	15.6	The synaptonemal complex forms after double-strand breaks 	426
	15.7	Pairing and synaptonemal complex formation are independent 	428
	15.8	The bacterial RecBCD system is stimulated by chi sequences 	429
	15.9	Strand-transfer proteins catalyze single-strand assimilation 	431
	15.10	The Ruv system resolves Holliday junctions 	433
	15.11	Gene conversion accounts for interallelic recombination 	434
	15.12	Supercoiling affects the structure of DNA 	436
	15.13	Topoisomerases relax or introduce supercoils in DNA 	438
	15.14	Topoisomerases break and reseal strands 	440
	15.15	Gyrase functions by coil inversion 	441
	15.16	Specialized recombination involves specific sites 	442
	15.17	Site-specific recombination involves breakage and reunion 	444
	15.18	Site-specific recombination resembles topoisomerase activity 	445
	15.19	Lambda recombination occurs in an intasome 	446
	15.20	Repair systems correct damage to DNA 	447
	15.21	Excision repair systems in E. coli 	450
	15.22	Base flipping is used by methylases and glycosylases 	451
	15.23	Error-prone repair and mutator phenotypes 	452
	15.24	Controlling the direction of mismatch repair 	453
	15.25	Recombination-repair systems in E. coli 	455
	15.26	Recombination is an important mechanism to recover from replication 
errors 	456
	15.27	RecA triggers the SOS system 	457
	15.28	Eukaryotic cells have conserved repair systems 	459
	15.29	A common system repairs double-strand breaks 	460
	15.30	Summary 	462
16 Transposons
	16.1	Introduction 	467
	16.2	Insertion sequences are simple transposition modules 	468
	16.3	Composite transposons have IS modules 	470
	16.4	Transposition occurs by both replicative and nonreplicative mechanisms 
	471
	16.5	Transposons cause rearrangement of DNA 	473
	16.6	Common intermediates for transposition 	474
	16.7	Replicative transposition proceeds through a cointegrate 	475
	16.8	Nonreplicative transposition proceeds by breakage and reunion 	476
	16.9	TnA transposition requires transposase and resolvase 	478
	16.10	Transposition of Tn10 has multiple controls 	480
	16.11	Controlling elements in maize cause breakage and rearrangements 	482
	16.12	Controlling elements form families of transposons 	483
	16.13	Spm elements influence gene expression 	486
	16.14	The role of transposable elements in hybrid dysgenesis 	487
	16.15	P elements are activated in the germline 	488
	16.16	Summary 	490
17 Retroviruses and retroposons
	17.1	Introduction 	493
	17.2	The retrovirus life cycle involves transposition-like events 	493
	17.3	Retroviral genes code for polyproteins 	494
	17.4	Viral DNA is generated by reverse transcription 	496
	17.5	Viral DNA integrates into the chromosome 	498
	17.6	Retroviruses may transduce cellular sequences 	499
	17.7	Yeast Ty elements resemble retroviruses 	500
	17.8	Many transposable elements reside in D. melanogaster 	502
	17.9	Retroposons fall into three classes 	504
	17.10	The Alu family has many widely dispersed members 	506
	17.11	Processed pseudogenes originated as substrates for transposition 	507
	17.12	LINES use an endonuclease to generate a priming end 	508
	17.13	Summary 	509
18 Rearrangement of DNA
	18.1	Introduction 	513
	18.2	The mating pathway is triggered by pheromone-receptor interactions 
	514
	18.3	The mating response activates a G protein 	515
	18.4	The signal is passed to a kinase cascade 	516
	18.5	Yeast can switch silent and active loci for mating type 	517
	18.6	The MAT locus codes for regulator proteins 	519
	18.7	Silent cassettes at HML and HMR are repressed 	521
	18.8	Unidirectional transposition is initiated by the recipient MAT locus 
	522
	18.9	Regulation of HO expression controls switching 	523
	18.10	Trypanosomes switch the VSG frequently during infection 	525
	18.11	New VSG sequences are generated by gene switching 	526
	18.12	VSG genes have an unusual structure 	528
	18.13	The bacterial Ti plasmid causes crown gall disease in plants 	529
	18.14	T-DNA carries genes required for infection 	530
	18.15	Transfer of T-DNA resembles bacterial conjugation 	532
	18.16	DNA amplification generates extra gene copies 	534
	18.17	Transfection introduces exogenous DNA into cells 	537
	18.18	Genes can be injected into animal eggs 	538
	18.19	ES cells can be incorporated into embryonic mice 	540
	18.20	Gene targeting allows genes to be replaced or knocked out 	541
	18.21	Summary 	542
Part 5 The Nucleus
19 Chromosomes
	19.1	Introduction 	545
	19.2	Viral genomes are packaged into their coats 	546
	19.3	The bacterial genome is a nucleoid 	549
	19.4	The bacterial genome is supercoiled 	550
	19.5	Eukaryotic DNA has loops and domains attached to a scaffold 	551
	19.6	Specific sequences attach DNA to an interphase matrix 	552
	19.7	Chromatin is divided into euchromatin and heterochromatin 	553
	19.8	Chromosomes have banding patterns 	555
	19.9	Lampbrush chromosomes are extended 	556
	19.10	Polytene chromosomes form bands 	557
	19.11	Polytene chromosomes expand at sites of gene expression 	558
	19.12	The eukaryotic chromosome is a segregation device 	559
	19.13	Centromeres have short DNA sequences in S. cerevisiae 	560
	19.14	The centromere binds a protein complex 	561
	19.15	Centromeres may contain repetitious DNA 	562
	19.16	Telomeres have simple repeating sequences 	563
	19.17	Telomeres seal the chromosome ends 	564
	19.18	Telomeres are synthesized by a ribonucleoprotein enzyme 	565
	19.19	Telomeres are essential for survival 	566
	19.20	Summary 	567
20 Nucleosomes
	20.1	Introduction 	571
	20.2	The nucleosome is the subunit of all chromatin 	572
	20.3	DNA is coiled in arrays of nucleosomes 	573
	20.4	Nucleosomes have a common structure 	574
	20.5	DNA structure varies on the nucleosomal surface 	576
	20.6	The periodicity of DNA changes on the nucleosome 	577
	20.7	The path of nucleosomes in the chromatin fiber 	578
	20.8	Organization of the histone octamer 	579
	20.9	The N-terminal tails of histones are modified 	581
	20.10	Reproduction of chromatin requires assembly of nucleosomes 	582
	20.11	Do nucleosomes lie at specific positions? 	585
	20.12	Are transcribed genes organized in nucleosomes? 	587
	20.13	Histone octamers are displaced by transcription 	588
	20.14	DNAase hypersensitive sites change chromatin structure 	590
	20.15	Domains define regions that contain active genes 	592
	20.16	An LCR may control a domain 	593
	20.17	Summary 	594
21 Promoters and enhancers
	21.1	Introduction 	597
	21.2	Eukaryotic RNA polymerases consist of many subunits 	599
	21.3	Promoter elements are defined by mutations and footprinting 	600
	21.4	RNA polymerase I has a bipartite promoter 	601
	21.5	RNA polymerase III uses both downstream and upstream promoters 	602
	21.6	TFIIIB is the commitment factor for pol III promoters 	603
	21.7	The startpoint for RNA polymerase II 	605
	21.8	TBP is a universal factor 	606
	21.9	TBP binds DNA in an unusual way 	607
	21.10	The basal apparatus assembles at the promoter 	608
	21.11	Initiation is followed by promoter clearance 	610
	21.12	A connection between transcription and repair 	611
	21.13	Short sequence elements bind activators 	613
	21.14	Promoter construction is flexible but context can be important 	614
	21.15	Enhancers contain bidirectional elements that assist initiation 	615
	21.16	Enhancers contain the same elements that are found at promoters 	616
	21.17	Enhancers work by increasing the concentration of activators near the 
promoter 	617
	21.18	Gene expression is associated with demethylation 	618
	21.19	CpG islands are regulatory targets 	620
	21.20	Insulators block the actions of enhancers and heterochromatin 	621
	21.21	Insulators can define a domain 	622
	21.22	Insulators may act in one direction 	623
	21.23	Insulators can vary in strength 	624
	21.24	What constitutes a regulatory domain? 	625
	21.25	Summary 	626
22 Activating transcription
	22.1	Introduction 	631
	22.2	There are several types of transcription factors 	632
	22.3	Independent domains bind DNA and activate transcription 	633
	22.4	The two hybrid assay detects protein-protein interactions 	635
	22.5	Activators interact with the basal apparatus 	636
	22.6	Some promoter-binding proteins are repressors 	638
	22.7	Response elements are recognized by activators 	639
	22.8	There are many types of DNA-binding domains 	641
	22.9	A zinc finger motif is a DNA-binding domain 	642
	22.10	Steroid receptors are activators 	643
	22.11	Steroid receptors have zinc fingers 	644
	22.12	Binding to the response element is activated by ligand-binding 	645
	22.13	Steroid receptors recognize response elements by a combinatorial code 
	646
	22.14	Homeodomains bind related targets in DNA 	647
	22.15	Helix-loop-helix proteins interact by combinatorial association 	649
	22.16	Leucine zippers are involved in dimer formation 	651
	22.17	Summary 	652
23 Controlling chromatin structure
	23.1	Introduction 	657
	23.2	Chromatin can have alternative states 	658
	23.3	Chromatin remodeling is an active process 	659
	23.4	Nucleosome organization may be changed at the promoter 	661
	23.5	Histone modification is a key event 	662
	23.6	Histone acetylation occurs in two circumstances 	663
	23.7	Acetylases are associated with activators 	665
	23.8	Deacetylases are associated with repressors 	666
	23.9	Methylation of histones and DNA is connected 	667
	23.10	Chromatin states are interconverted by modification 	668
	23.11	Promoter activation involves an ordered series of events 	668
	23.12	Histone phosphorylation affects chromatin structure 	669
	23.13	Heterochromatin propagates from a nucleation event 	670
	23.14	Some common motifs are found in proteins that modify chromatin 	671
	23.15	Heterochromatin depends on interactions with histones 	672
	23.16	Polycomb and trithorax are antagonistic repressors and activators 	674
	23.17	X chromosomes undergo global changes 	676
	23.18	Chromosome condensation is caused by condensins 	678
	23.19	DNA methylation is perpetuated by a maintenance methylase 	680
	23.20	DNA methylation is responsible for imprinting 	681
	23.21	Oppositely imprinted genes can be controlled by a single center 	683
	23.22	Epigenetic effects can be inherited 	683
	23.23	Yeast prions show unusual inheritance 	685
	23.24	Prions cause diseases in mammals 	687
	23.25	Summary 	689
24 RNA splicing and processing
	24.1	Introduction 	697
	24.2	Nuclear splice junctions are short sequences 	698
	24.3	Splice junctions are read in pairs 	699
	24.4	pre-mRNA splicing proceeds through a lariat 	701
	24.5	snRNAs are required for splicing 	702
	24.6	U1 snRNP initiates splicing 	704
	24.7	The E complex can be formed by intron definition or exon definition 
	706
	24.8	5 snRNPs form the spliceosome 	707
	24.9	An alternative splicing apparatus uses different snRNPs 	709
	24.10	Splicing is connected to export of mRNA 	709
	24.11	Group II introns autosplice via lariat formation 	710
	24.12	Alternative splicing involves differential use of splice junctions 
	712
	24.13	trans-splicing reactions use small RNAs 	714
	24.14	Yeast tRNA splicing involves cutting and rejoining 	716
	24.15	The splicing endonuclease recognizes tRNA 	717
	24.16	tRNA cleavage and ligation are separate reactions 	718
	24.17	The unfolded protein response is related to tRNA splicing 	719
	24.18	The 3¢ ends of polI and polIII transcripts are generated by termination 
	720
	24.19	The 3¢ ends of mRNAs are generated by cleavage and polyadenylation 
	721
	24.20	Cleavage of the 3¢ end of histone mRNA may require a small RNA 	723
	24.21	Production of rRNA requires cleavage events 	723
	24.22	Small RNAs are required for rRNA processing 	724
	24.23	Summary 	725
25 Catalytic RNA
	25.1	Introduction 	731
	25.2	Group I introns undertake self-splicing by transesterification 	732
	25.3	Group I introns form a characteristic secondary structure 	734
	25.4	Ribozymes have various catalytic activities 	735
	25.5	Some group I introns code for endonucleases that sponsor mobility 	737
	25.6	Some group II introns code for reverse transcriptases 	739
	25.7	The catalytic activity of RNAase P is due to RNA 	740
	25.8	Viroids have catalytic activity 	740
	25.9	RNA editing occurs at individual bases 	742
	25.10	RNA editing can be directed by guide RNAs 	743
	25.11	Protein splicing is autocatalytic 	746
	25.12	Summary 	747
26 Immune diversity
	26.1	Introduction 	751
	26.2	Clonal selection amplifies lymphocytes that respond to individual 
antigens 	753
	26.3	Immunoglobulin genes are assembled from their parts in lymphocytes 
	754
	26.4	Light chains are assembled by a single recombination 	757
	26.5	Heavy chains are assembled by two recombinations 	758
	26.6	Recombination generates extensive diversity 	759
	26.7	Immune recombination uses two types of consensus sequence 	760
	26.8	Recombination generates deletions or inversions 	761
	26.9	The RAG proteins catalyze breakage and reunion 	762
	26.10	Allelic exclusion is triggered by productive rearrangement 	765
	26.11	Class switching is caused by DNA recombination 	766
	26.12	Switching occurs by a novel recombination reaction 	768
	26.13	Early heavy chain expression can be changed by RNA processing 	769
	26.14	Somatic mutation generates additional diversity in mouse and man 	770
	26.15	Somatic mutation is induced by cytidine deaminase and uracil glycosylase 
	771
	26.16	Avian immunoglobulins are assembled from pseudogenes 	773
	26.17	B cell memory allows a rapid secondary response 	774
	26.18	T cell receptors are related to immunoglobulins 	775
	26.19	The T cell receptor functions in conjunction with the MHC 	777
	26.20	The major histocompatibility locus codes for many genes of the immune 
system 	778
	26.21	Innate immunity utilizes conserved signaling pathways 	781
	26.22	Summary 	783
Part 6 Cells
27 Protein trafficking
	27.1	Introduction 	787
	27.2	Oligosaccharides are added to proteins in the ER and Golgi 	788
	27.3	The Golgi stacks are polarized 	790
	27.4	Coated vesicles transport both exported and imported proteins 	790
	27.5	Different types of coated vesicles exist in each pathway 	792
	27.6	Cisternal progression occurs more slowly than vesicle movement 	795
	27.7	Vesicles can bud and fuse with membranes 	796
	27.8	The exocyst tethers vesicles by interacting with a Rab 	797
	27.9	SNARES are responsible for membrane fusion 	798
	27.10	The synapse is a model system for exocytosis 	800
	27.11	Protein localization depends on specific signals 	800	
	27.12	ER proteins are retrieved from the Golgi 	802
	27.13	Brefeldin A reveals retrograde transport 	803
	27.14	Vesicles and cargos are sorted for different destinations 	804
	27.15	Receptors recycle via endocytosis 	804
	27.16	Internalization signals are short and contain tyrosine 	806
	27.17	Summary 	807
28 Signal transduction
	28.1	Introduction 	811
	28.2	Carriers and channels form water soluble paths through the membrane 
	813
	28.3	Ion channels are selective 	814
	28.4	Neurotransmitters control channel activity 	816
	28.5	G proteins may activate or inhibit target proteins 	817
	28.6	G proteins function by dissociation of the trimer 	818
	28.7	Protein kinases are important players in signal transduction 	819
	28.8	Growth factor receptors are protein kinases 	821
	28.9	Receptors are activated by dimerization 	822
	28.10	Receptor kinases activate signal transduction pathways 	823
	28.11	Signaling pathways often involve protein-protein interactions 	824
	28.12	Phosphotyrosine is the critical feature in binding to an SH2 domain 
	825
	28.13	Prolines are important determinants in recognition sites 	826
	28.14	The Ras/MAPK pathway is widely conserved 	827
	28.15	The activation of Ras is controlled by GTP 	829
	28.16	A MAP kinase pathway is a cascade 	830
	28.17	What determines specificity in signaling? 	832
	28.18	Activation of a pathway can produce different results 	834
	28.19	Cyclic AMP and activation of CREB 	835
	28.20	The JAK-STAT pathway 	836
	28.21	TGFb signals through Smads 	838
	28.22	Summary 	839
29 Cell cycle and growth regulation
	29.1	Introduction 	843
	29.2	Cycle progression depends on discrete control points 	844
	29.3	Checkpoints occur throughout the cell cycle 	845
	29.4	Cell fusion experiments identify cell cycle inducers 	846
	29.5	M phase kinase regulates entry into mitosis 	848
	29.6	M phase kinase is a dimer of a catalytic subunit and a regulatory cyclin 
	849
	29.7	Protein phosphorylation and dephosphorylation control the cell cycle 
	851
	29.8	Many cell cycle mutants have been found by screens in yeast 	853
	29.9	Cdc2 is the key regulator in yeasts 	854
	29.10	Cdc2 is the only catalytic subunit of the cell cycle activators in S. 
pombe 	855
	29.11	CDC28 acts at both START and mitosis in S. cerevisiae 	856
	29.12	Cdc2 activity is controlled by kinases and phosphatases 	858
	29.13	DNA damage triggers a checkpoint 	861
	29.14	The animal cell cycle is controlled by many cdk-cyclin complexes 	863
	29.15	Dimers are controlled by phosphorylation of cdk subunits and by 
availability 
of cyclin subunits 	864
	29.16	RB is a major substrate for cdk-cyclin complexes 	866
	29.17	G0/G1 and G1/S transitions involve cdk inhibitors 	867
	29.18	Protein degradation is important in mitosis 	868
	29.19	Cohesins hold sister chromatids together 	869
	29.20	Exit from mitosis is controlled by the location of Cdc14	871
	29.21	The cell forms a spindle at mitosis 	871
	29.22	The spindle is oriented by centrosomes 	873
	29.23	A monomeric G protein controls spindle assembly 	874
	29.24	Daughter cells are separated by cytokinesis 	875
	29.25	Apoptosis is a property of many or all cells 	876
	29.26	The Fas receptor is a major trigger for apoptosis 	876
	29.27	A common pathway for apoptosis functions via caspases 	878	
	29.28	Apoptosis involves changes at the mitochondrial envelope 	879
	29.29	Cytochrome c activates the next stage of apoptosis 	880
	29.30	There are multiple apoptotic pathways 	882
	29.31	Summary 	882
30 Oncogenes and cancer
	30.1	Introduction 	889
	30.2	Tumor cells are immortalized and transformed 	890
	30.3	Oncogenes and tumor suppressors have opposite effects 	892
	30.4	Transforming viruses carry oncogenes 	893
	30.5	Early genes of DNA transforming viruses have multifunctional oncogenes 
	893
	30.6	Retroviruses activate or incorporate cellular genes 	895
	30.7	Retroviral oncogenes have cellular counterparts 	896
	30.8	Quantitative or qualitative changes can explain oncogenicity 	898
	30.9	Ras oncogenes can be detected in a transfection assay 	899
	30.10	Ras proto-oncogenes can be activated by mutation at specific positions 
	900
	30.11	Nondefective retroviruses activate proto-oncogenes 	901
	30.12	Proto-oncogenes can be activated by translocation 	902
	30.13	The Philadelphia translocation generates a new oncogene 	904
	30.14	Oncogenes code for components of signal transduction cascades 	905
	30.15	Growth factor receptor kinases can be mutated to oncogenes 	907
	30.16	Src is the prototype for the proto-oncogenic cytoplasmic tyrosine 
kinases 	909
	30.17	Src activity is controlled by phosphorylation 	910
	30.18	Oncoproteins may regulate gene expression 	912
	30.19	RB is a tumor suppressor that controls the cell cycle 	915
	30.20	Tumor suppressor p53 suppresses growth or triggers apoptosis 	917
	30.21	p53 is a DNA-binding protein 	919
	30.22	p53 is controlled by other tumor suppressors and oncogenes 	921
	30.23	p53 is activated by modifications of amino acids 	922
	30.24	Telomere shortening causes cell senescence 	923
	30.25	Immortalization depends on loss of p53	925
	30.26	Different oncogenes are associated with immortalization and 
transformation 	926
	30.27	p53 may affect ageing 	929
	30.28	Genetic instability is a key event in cancer 	930
	30.29	Defects in repair systems cause mutations to accumulate in tumors 	931
	30.30	Summary 	932
31 Gradients, cascades, and signaling pathways
	31.1	Introduction 	939
	31.2	Fly development uses a cascade of transcription factors 	940
	31.3	A gradient must be converted into discrete compartments 	941
	31.4	Maternal gene products establish gradients in early embryogenesis 	943
	31.5	Anterior development uses localized gene regulators 	945
	31.6	Posterior development uses another localized regulator 	946
	31.7	How are mRNAs and proteins transported and localized? 	948
	31.8	How are gradients propagated? 	949
	31.9	Dorsal-ventral development uses localized receptor-ligand interactions 
	950
	31.10	Ventral development proceeds through Toll 	951
	31.11	Dorsal protein forms a gradient of nuclear localization 	953
	31.12	Patterning systems have common features 	955
	31.13	TGFb/BMPs are diffusible morphogens 	956
	31.14	Cell fate is determined by compartments that form by the blastoderm 
stage 	957
	31.15	Gap genes are controlled by bicoid and by one another 	959
	31.16	Pair-rule genes are regulated by gap genes 	960
	31.17	Segment polarity genes are controlled by pair-rule genes 	961
	31.18	Wingless and engrailed expression alternate in adjacent cells 	963
	31.19	The wingless/wnt pathway signals to the nucleus 	964
	31.20	Complex loci are extremely large and involved in regulation 	965
	31.21	The bithorax complex has trans-acting genes and cis-acting regulators 
	968
	31.22	The homeobox is a common coding motif in homeotic genes 	972
	31.23	Summary 	975
Glossary	981
Index	1003
 

Library of Congress Subject Headings for this publication: Genetics, Genes, Genes physiology, Cell Physiology, DNA genetics, Genetic Processes, Proteins genetics, RNA genetics