Replicating And Repairing The Genome: From Basic Mechanisms To Modern Genetic Technologies

Replicating And Repairing The Genome: From Basic Mechanisms To Modern Genetic Technologies
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Replicating and Repairing the Genome provides a concise overview of the fields of DNA replication and repair. The book is particularly appropriate for graduate students and advanced undergraduates, and scientists entering the field or working in related fields. The breadth of information regarding DNA replication and repair is vast and often difficult to absorb, with terminology that differs between experimental systems and with complex interconnections of these processes with other cellular pathways. This book provides simple conceptual descriptions of replication and repair pathways using mostly generic protein names, laying out the logic for how the pathways function and highlighting fascinating aspects of the underlying biochemical mechanisms and biology. The book incorporates extensive and informative diagrams and figures, as well as descriptions of a number of carefully chosen experiments that had major influences in the field. The process of DNA replication is explained progressively by starting with the system of a simple bacterial virus that uses only a few proteins, followed by the well-understood bacterial ( E coli ) system, and then culminating with the more complex eukaryotic systems. In the second half of the book, individual chapters cover key areas of DNA repair — postreplication repair of mismatches and incorporated ribonucleotides, direct damage reversal, excision repair, and DNA break repair, as well as the related areas of DNA damage tolerance (including translesion DNA polymerases) and DNA damage responses. The book closes with chapters that describe the huge impact of DNA replication and repair on aspects of human health and on modern biotechnology. Contents: The Challenges of Maintaining and Duplicating the GenomeThe Simple DNA Replication System of a Bacterial VirusThe Highly Efficient Replication System of BacteriaEukaryotic DNA ReplicationReplication Dynamics — Initiating, Regulating and Terminating Cellular DNA ReplicationPostreplication Repair of Mismatches and RibonucleotidesDNA Topology and the Enzymes That Alter ItDNA Damage — A Persistent Threat to the GenomeDirect Reversal of DNA DamageExcision Repair — Taking Advantage of the Complementary StrandRepair of Double-Strand BreaksDNA Damage Tolerance and Translesion DNA PolymerasesDNA Damage Response PathwaysDNA Replication and Repair in Human DiseaseEnzymes of DNA Replication and Repair Fuel Modern Genomic Technologies Readership: Graduate students, advanced undergraduates and scientists in the field of oncology/cancer biology.Replication;DNA Repair;Recombination;DNA;Biotechnology;Basic Research;DNA Damage;DNA Polymerase;DNA Helicase;Topoisomerase0 Key Features: As described above, the book provides a broad overview of the fields of DNA replication and repair without diving deeply into the many complexities of mechanism and terminology that are common in review articles and other books in these areas. The book carefully builds up a sophisticated understanding of the detailed mechanisms in replication and repair by introducing simple systems first, and adding layers of complexity without resorting to excessive technical jargon. Throughout the book, mechanisms and principles are illustrated with informative Figures and TablesThe process of discovery in science and the construction of informative and rigorous experiments are, for many, the most compelling aspects of being a scientist. In this book, experimental approaches are integrated into the text at times, and also augmented with side boxes that illustrate particularly interesting and/or historically important experiments. These side boxes are called «How was that tested?», and a subset illustrate the progression of scientific methodology with a «Then and Now» theme. Side boxes also highlight experimental findings that resulted in Nobel Prizes. These various side boxes are very useful when the book is adopted for a course — the course work can expand on the side box by discussing more of the experiments in that particular study, they can be used as an introduction to modern technologies in genetics, biochemistry and cell biology, and they can be used as jumping-off points for student presentations (oral or written) or for group discussionsThe author is an accomplished scientist/educator who has published over 100 research articles in the fields of DNA replication and repair, funded by extensive research grants from the NIH and other agencies. Dr Kreuzer is a Fellow of the American Academy of Microbiology and the American Association for the Advancement of Science. He has mentored high school, college, graduate and post-graduate students, and has taken a very active role in recruiting and mentoring students from underrepresented groups. Most relevant to this book, Dr Kreuzer has taught the principles of DNA replication and repair to undergraduate, graduate and medical students during his 30-year career at Duke University. In honor of his teaching and mentoring, he won the first Duke University Faculty Award for Graduate Teaching in the Basic Biomedical Sciences (2001)

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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

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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.

.....

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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