Replicating And Repairing The Genome: From Basic Mechanisms To Modern Genetic Technologies
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Kenneth N Kreuzer. Replicating And Repairing The Genome: From Basic Mechanisms To Modern Genetic Technologies
Dedication
Preface
Acknowledgments
Contents
About the Author
Chapter 1. The challenges of maintaining and duplicating the genome. 1.1Introduction
1.2The double-helical structure of DNA and the logic of replication and repair
1.3The key functions needed for the process of DNA replication
1.4Repairing and tolerating damage to the DNA molecule
1.5Summary of key points
Further Reading
How did they test that? The base composition of DNA and Chargaff’s rule
Chapter 2. The simple DNA replication system of a bacterial virus. 2.1Why the interest in a bacterial virus?
2.2The four proteins involved in T7 DNA replication
2.3Activities of T7 DNA polymerase in the replisome
2.4Mechanisms of unwinding by the T7 helicase
2.5The replisome machine functions with a looped lagging-strand template
2.6Structural model for the T7 replisome
2.7T7 ssDNA-binding protein helps to organize the replisome
2.8Finalizing the lagging-strand product
2.9Back to the beginning — How does T7 DNA replication initiate?
2.10Summary of key points
Further Reading
How did they test that? Are leading- and lagging-strand synthesis coupled?
Chapter 3. The highly efficient replication system of bacteria
3.1The E. coli replisome from 30,000 feet
3.2The replicative DNA polymerase holoenzyme
3.3Dynamics of clamp loading in bacterial replication
3.4Coordinated action of helicase, primase, and DNA polymerase holoenzyme
3.5The E. coli ssDNA-binding protein
3.6Housekeeping after the replisome passes — Repairing Okazaki fragments, reducing replicative errors, and recycling clamps from the DNA
3.7Replication restart and other rescue pathways
3.8Summary of key points
Further Reading
How did they test that? Does the sliding clamp encircle DNA?
Chapter 4. Eukaryotic DNA replication
4.1Special challenges of replicating multiple linear chromosomes
4.2How do eukaryotic replication proteins compare to their prokaryotic counterparts?
4.3MCM complex — the replicative helicase in eukaryotes
4.4Eukaryotic primase is a component of polymerase α
4.5Specialized polymerases for the leading and lagging strand
4.6The eukaryotic clamp and clamp loader
4.7RPA — the eukaryotic ssDNA-binding protein
4.8Coordination of the fork and the trombone model
4.9Continuing DNA replication past template lesions that block replicative polymerases
4.10Events after the fork passes
4.11Summary of key points
Further Reading
How did they test that? Which DNA polymerase synthesizes the leading strand in yeast?
Chapter 5. Replication dynamics — initiating, regulating and terminating cellular DNA replication
5.1Defining the bacterial replication origin
5.2Initiating DNA replication in bacteria
5.3Regulation of origin firing in bacteria
5.4Termination of replication in E. coli
5.5Location of replication origins in eukaryotes
5.6The overall logic of origin usage in eukaryotes — many are licensed but (relatively) few are fired
5.7Licensing during the G1 phase
5.8Assembly of the complete replication machinery and origin firing
5.9Completing replication: Converging forks and the replication checkpoint
5.10Telomeres and their replication
5.11Summary of key points
Further Reading
How did they test that? Isolation of ORC, the eukaryotic replicationinitiation protein
Chapter 6. Postreplication repair of mismatches and ribonucleotides
6.1The overall function and logic of post-replicative MMR
6.2Methyl-directed MMR in E. coli
6.3Eukaryotic MMR
6.4Additional functions of MMR
6.5MMR defects in cancer
6.6Postreplicative repair of incorporated ribonucleotide residues
6.7Summary of key points
Further Reading
How did they test that? Reconstitution of methyl-directed mismatch repair in vitro
Chapter 7. DNA topology and the enzymes that alter it. 7.1The superhelical structure of duplex DNA
7.2The helical and superhelical dilemma of replicating DNA
7.3DNA topoisomerases to the rescue
7.4The sources of negative supercoiling inside cells
7.5Subversion of topoisomerases as a potent tool in chemotherapy
7.6Summary of key points
Further Reading
How did they test that? Type II DNA topoisomerases change linking number in steps of two
Chapter 8. DNA damage — a persistent threat to the genome. 8.1Introduction
8.2Damage, repair, and mutation
8.3Spontaneous DNA damage
8.4Damage induced by exogenous chemicals
8.5Radiation-induced DNA damage
8.6DNA damage by incorporation of damaged nucleotides
8.7DNA damage from cellular enzymes
8.8Summary of key points
Further Reading
How did they test that? Detecting DNA damage in cells — the comet assay
Chapter 9. Direct reversal of DNA damage
9.1Photoreactivation of UV-induced damage
9.2Reversal of alkylation damage by DNA alkyl transferases
9.3Reversal of alkylation damage by dioxygenases
9.4Summary of key points
Further Reading
How did they test that? Does O6-methylguanine DNA methyltransferase protect mice from alkylating agents?
Chapter 10. Excision repair — taking advantage of the complementary strand
10.1Repair of AP sites
10.2Repair of uracil residues in DNA — the prototype BER pathway
10.3Diverse DNA glycosylases expand the repertoire of BER
10.4Bacterial NER repairs UV-induced dimers and other bulky lesions
10.5NER in eukaryotic systems
10.6TC-NER repairs lesions that have blocked RNA polymerase
10.7Summary of key points
Further Reading
How did they test that? What are the excision products of NER?
Chapter 11. Repair of double-strand breaks
11.1The machinery at the heart of homologous recombination
11.2Homologous recombination in genetic exchange and meiosis
11.3Holliday junctions and pathways that process them
11.4The final stages of meiotic recombination
11.5Repair of DSBs by homologous recombination in mitotic cells
11.6Connections between homologous recombination and DNA replication
11.7The machinery of c-NHEJ
11.8Biological roles of c-NHEJ
11.9Pathway choice in DSB repair
11.10SSA and alt-NHEJ
11.11Summary of key points
Further Reading
How did they test that? Does the MRN (MRX) complex promote end tethering?
Chapter 12. DNA-damage tolerance and translesion DNA polymerases
12.1Damage tolerance by template switching
12.2An active process is often needed for mutagenesis
12.3The riddles of DNA polymerases that disregard normal base-pairing rules
12.4Introduction to translesion DNA polymerases
12.5Translesion DNA polymerases in E. coli
12.6Eukaryotic translesion DNA polymerases
12.7One-step versus two-step pathways
12.8Control of translesion synthesis in eukaryotic cells
12.9Biological importance of translesion DNA polymerases
12.10Summary of key points
Further Reading
How did they test that? Does yeast Rad30 protein have DNA polymerase activity on damaged templates?
Chapter 13. DNA-damage response pathways
13.1The bacterial SOS response
13.2DNA damage in eukaryotes alters cell fates: Checkpoints, apoptosis, and necrosis
13.3Activation and regulatory circuitry of the eukaryotic DDR
13.4DDR activation alters both transcription and posttranslational events
13.5DNA-repair pathways are activated by the DDR
13.6The process of DNA replication is renovated by the DDR
13.7Chromatin structure and behavior change during the DDR
13.8Summary of key points
Further Reading
How did they test that? Double-strand breaks induce nearby patch of phosphorylated H2AX
Chapter 14. DNA replication and repair in human disease
14.1Inherited defects in replication machinery cause developmental defects
14.2Dozens of human diseases relate to inherited mitochondrial defects
14.3Nucleotide-repeat expansions cause neurological and developmental diseases
14.4Predisposition to sunlight-induced cancers due to NER deficiency
14.5MMR defects cause predisposition to colon cancer
14.6Complex developmental/cancer syndromes caused by helicase deficiencies
14.7Mutations in DSB repair and DDR pathways cause complex syndromes
14.8Insights from molecular analysis of sporadic tumors
14.9Anticancer therapy — traditional and gene based
14.10Summary of key points
Further Reading
How did they test that? Triplet-repeat expansion is the basis for Huntington’s disease
Chapter 15. Enzymes of DNA replication and repair fuel modern genomic technologies
15.1Commercialization of proteins and enzymes that act on DNA
15.2The PCR revolution
15.3Constructing recombinant DNA molecules and synthetic biology
15.4First-generation DNA-sequencing technology
15.5Next-generation DNA-sequencing technologies
15.6Expansive applications of high-throughput DNA sequencing
15.7Summary of key points
Further Reading
How did they test that? DNA sequence of bacteriophage λ
Appendix
Index
Отрывок из книги
This book is dedicated to two outstanding scientists who contributed greatly to the field during their lives and strongly impacted my career. Unfortunately, both passed away much too soon. As my graduate school mentor, Nick Cozzarelli taught me a great deal about conducting experimental science and sustaining a critical attitude about advances in the field. For many years, Tao Hsieh was a wonderful colleague with whom I enjoyed discussions, sharing teaching and other responsibilities, and collaborating. Both Nick and Tao were master biochemists with a phenomenal understanding of both DNA replication and DNA topology, and both are sorely missed.
While the main text will generally not attempt to provide the experimental designs and details behind the science, inserts called “How did they test that?” are included at the end of each chapter to illustrate some of the beautiful experimental approaches that uncovered key aspects of DNA replication and repair. These can be jumping-off points for readers to delve into primary literature in the field.
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Chargaff, E., Lipshitz, R., & Green, C. (1952). Composition of the desoxypentose nucleic acids of four genera of sea-urchin. J Biol Chem, 195(1), 155–160.
DePamphilis, M. L., & Bell, S. D. (2011). Genome Duplication. New York, NY: Garland Science.
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