Main description:

High-fidelity chromosomal DNA replication underpins all life on the planet. In humans, there are clear links between chromosome replication defects and genome instability, genetic disease and cancer, making a detailed understanding of the molecular mechanisms of genome duplication vital for future advances in diagnosis and treatment. Building on recent exciting advances in protein structure determination, the book will take the reader on a guided journey through the intricate molecular machinery of eukaryotic chromosome replication and provide an invaluable source of information, ideas and inspiration for all those with an interest in chromosome replication, whether from a basic science, translational biology and medical research perspective.

Contents:

Preface

1. Composition and dynamics of the eukaryotic replisome: a brief overview; Stuart A. MacNeill
1.1 Introduction
1.2 Replication origins and the origin recognition complex
1.3 Formation of the pre-RC at origins
1.4 The replisome progression complex
1.5 The replicative polymerases
1.6 Sliding clamp and clamp loader complexes
1.7 Okazaki fragment processing
1.8 Model systems for the studying eukaryotic replication
1.8.1 SV40
1.8.2 Yeast
1.8.3 Xenopus
1.8.4 Archaea
1.8.5 Other model systems
1.9 Conclusions
Acknowledgements
References

2. Evolutionary diversification of eukaryotic DNA replication machinery; Stephen J. Aves, Yuan Liu and Thomas A. Richards
2.1 Introduction
2.2 Eukaryotic diversity
2.3 Conservation of replisome proteins
2.4 Indispensable replisome proteins
2.5 Replisome proteins present in all eukaryotic supergroups
2.6 Replisome proteins not present in all supergroups
2.7 A complex ancestral replisome
2.8 Conclusions
References

3. The origin recognition complex: a biochemical and structural view; Huilin Li and Bruce Stillman
3.1 Introduction
3.2 The S. cerevisiae ORC
3.3 The S. pombe ORC
3.4 The D. melanogaster ORC
3.5 The H. sapiens ORC
3.6 Future perspectives
Acknowledgements
References

4. Archaeal Orc1/Cdc6 Proteins; Stephen D. Bell
4.1 Introduction
4.2 Origins of DNA replication in the Archaea
4.3 Orc1/Cdc6 Structure
4.4 Structures of Orc1/Cdc6 bound to DNA
4.5 Beyond binding origins - what do Orc1/Cdc6s do?Acknowledgements
References

5. Cdt1 and Geminin in DNA replication initiation; Christophe Caillat and Anastassis Perrakis
5.1 Cdt1 and Geminin: a functional preview5.2 The multiple faces of Geminin
5.2.1 Geminin functions in replication licensing
5.2.2 Geminin in the cell cycle
5.2.3 Geminin in cell differentiation
5.3 The structure of Geminin
5.3.1 The N-terminal domain
5.3.2 The coiled-coil domain
5.4 The structure of Cdt1
5.4.1 The N-terminal domain is highly regulated
5.4.2 The structurally conserved winged helix domains
5.4.3 The recruitment of Cdt1 on chromatin
5.5 The Cdt1-Geminin complex
5.5.1 The primary and secondary interfaces
5.5.2 The tertiary interface
5.5.3 Conformational change of the N-terminal domain?
5.6 Models for a Cdt1-Geminin molecular switch
5.7 Conclusions
References

6. MCM structure and mechanics: what we have learned from archaeal MCM: Ian M. Slaymaker and Xiaojiang S. Chen
6.1 Introduction
6.2 Complex organization: Hexamers and double hexamers
6.3 Helicase activity
6.3.1 Steric exclusion
6.3.2 Ploughshare
6.3.3 LTag looping model (or strand exclusion)
6.3.4 Rotary pump
6.4 Domains and features of an MCM subunit
6.4.1 N domain
6.4.2 C domain
6.4.2.1 ATP binding pocket
6.4.2.2 Hairpins, helices and inserts
6.4.2.3 Winged helix domain
6.5 Inter- and intra-subunit communication
6.6 Higher-order MCM oligomers
6.7 Conclusions
References

7. The Eukaryotic Mcm2-7 Replicative Helicase; Sriram Vijayraghavan and Anthony Schwacha
7.1 Introduction
7.2 The 'Mcm problem' and nonequivalent ATPase active sites
7.3 Discovery of Mcm2-7 helicase activity and the Mcm2/5 gate
7.3.1 Differences in circular ssDNA binding between Mcm2-7 and Mcm467
7.3.2 An in vitro condition that 'closes' Mcm2-7 stimulates its helicase activity
7.3.3 The Mcm2/5 'gate' model - the open conformation and DNA unwinding are mutually exclusive
7.4 The CMG complex
7.4.1 Discovery of the CMG complex
7.4.2 CMG structure - Cdc45 and GINS close the Mcm2/5 gate
7.4.3 Possible regulation of the Mcm2/5 gate
7.5 How does Mcm2-7 unwind DNA?
7.5.1 Mcm2-7 loads as double hexamers onto dsDNA
7.5.2 Single-molecule studies eliminate the dsDNA pump model for elongation
7. 6 Speculative model for Mcm2-7 function
Acknowledgements
References

8. The GINS complex: structure and function; Katsuhiko Kamada
8.1 Introduction
8.2 Discovery of GINS
8.3 GINS functions
8.3.1 Replication initiation in the budding yeast
8.3.2 Replication initiation in the fission yeast
8.3.3 Replication initiation in higher eukaryotes
8.3.4 GINS in the replication progression complex
8.4 Structure of GINS
8.4.1 Overall structure
8.4.2 Two structural domains in all subunits
8.4.3 Functional interface of the GINS complex
8.4.4 GINS and the CMG complex
8.4.5 EM images and DNA clamping action
8.5 Archaeal GINS
8.5.1 Structure and evolution
8.5.2 Biological functions of archaeal GINS
8.6 Conclusions and prospects
Acknowledgments
References

9. The Pol -primase complex; Luca Pellegrini
9.1 Introduction
9.2 Primase
9.2.1 Prim fold of the catalytic subunit
9.2.2 The archaeal/eukaryotic primase is an iron-sulfur protein
9.3 DNA polymerase
9.3.1 Catalytic activity
9.3.2 Structure of the B subunit and its interaction with Pol
9.4 Towards a concerted mechanism for primer synthesis by the Pol -primase complex
9.5 Outlook
References

10. The structure and function of replication protein A in DNA replication; Aishwarya Prakash and Gloria E. O. Borgstahl
10.1 Introduction
10.2 Evolution of RPA
10.3 RPA structure
10.4 Interactions of RPA with single-stranded DNA
10.5 DNA structure and requirement for RPA
10.6 RPA binding to non-canonical DNA structures
10.7 RPA binding to damaged DNA
10.8 Role in recruiting proteins to the replication fork
10.9 Concluding remarks - future research on RPA
Acknowledgements
References

11. Structural biology of replication initiation factor Mcm10; Wenyue Du, Melissa E. Stauffer and Brandt F. Eichman
11.1 Replication initiation
11.2 Role of Mcm10 in replication
11.3 Overall architecture
11.4 Mcm10 domain structure
11.4.1 Mcm10-NTD
11.4.2 Mcm10-ID
11.4.3 Mcm10-CTD
11.5 Implications of modular architecture for function
11.6 Summary and future perspectives
References

12. Structure and function of eukaryotic DNA polymerase d; Tahir H. Tahirov
12.1 Introduction
12.2 Catalytic subunit (A-subunit)
12.2.1 Crystal structure of catalytic core
12.2.2 Cancer-causing mutations
12.2.3 C-terminal domain
12.2.4 Similarities between C-terminal domains of Pol d and Pol z
12.3 B- and C-subunits
12.3.1 Crystal structure of p50 p66N
12.3.2 p50 p66 Interactions
12.3.3 Functional studies
12.3.4 Crystal structure of p66*PCNA
12.4 D-subunit
12.4.1 D-subunit structure and inter-subunit interactions
12.4.2 D-subunit function
12.5 Conclusions and prospects
References

13. DNA polymerase ; Matthew Hogg and Erik Johansson
13.1 Introduction
13.2 Structure of Pol subunits
13.2.1 Pol2
13.2.2 Dpb2
13.2.3 Dpb3/Dpb4 dimer
13.3 Structure of Pol holoenzyme
13.4 Higher order structures 13.4.1 Initiation of DNA replication
13.4.2 Role at the replication fork
13.4.3 PCNA
13.4.4 Checkpoint activation in S phase
13.5 Ribose vs deoxyribose discrimination
13.6 Concluding remarks
Acknowledgements
References

14. The RFC clamp loader: structure and function; Nina Y. Yao and Mike O'Donnell
14.1 Overview of clamp loaders and sliding clamps
14.2 Clamp loader structure
14.3 RFC clamp loader interaction with DNA
14.4 ATP binding and opening of the clamp
14.5 ATP hydrolysis and closing of the clamp
14.6 Clamp loaders also unload clamps after replication
14.7 Alternative RFCs
14.8 Conclusions
References

15. PCNA structure and function: insights from structures of PCNA complexes and post-translationally modified PCNA; Lynne M. Dieckman, Bret D. Freudenthal and M. Todd Washington
15.1 Introduction
15.2 Structure of PCNA
15.3 Structures of PCNA complexes
15.3.1 Structures of PCNA bound to PIP peptides
15.3.2 Structures of PCNA bound to full-length proteins
15.3.3 Low resolution structures of PCNA complexes
15.3.4 Unresolved issues
15.4 Structures of mutant PCNA proteins
15.5 Structures of post-translationally modified PCNA
15.5.1 Structure of ubiquitin-modified PCNA
15.5.2 Structure of SUMO-modified PCNA
15.6 Concluding remarks
Acknowledgements
References

16. The wonders of Flap Endonucleases: structure, function, mechanism and regulation; L. David Finger, John M. Atack, Susan Tsutakawa, Scott Classen, John Tainer, Jane Grasby, Binghui Shen
16.1 Introduction
16.2 Biochemical activity
16.3 FEN structure and substrate recognition
16.3.1 Free protein
16.3.2 Protein-product and protein-substrate complexes
16.3.3 Protein product complex 5'-strand interactions
16.3.4 Protein substrate complex 5'-flap strand interactions
16.3.5 Bind-then-thread or bind-then-clamp
16.3.6 Scissile phosphate placement: the double nucleotide unpairing trap (DoNUT)
16.3.7 Cleavage of the scissile phosphate diester: active site structure
16.4 Regulation of FEN1 Activity
16.4.1 Protein-protein interactions
16.4.1.1 PCNA
16.4.1.2 RecQ helicase family interactions
16.4.2 Post-translational Modifications
16.5 Handoff of DNA intermediates
Acknowledgements
References

17. DNA ligase I, the replicative DNA ligase; Timothy R.L. Howes, Alan E. Tomkinson
17.1 Introduction
17.2 Eukaryotic DNA ligase genes
17.3 DNA ligase I: molecular genetics and cell biology
17.4 DNA ligase I protein: structure and function
17.5 DNA ligase I: protein interactions
17.6 Concluding remarks
References