Preface

DNA replication is a fundamental part of the life cycle of all organisms. Not surprisingly many aspects of this process display profound conservation across organisms in all domains of life. Successful duplication of the genetic material can decide the life or death of an organ‐ ism. Hence, the integrity of the DNA replication process is paramount and any defects or errors can lead to a myriad of problems ranging from cell death and developmental failure to increased propensity for cancer.

The importance of accurately regulating the initiation and progression of DNA synthesis is reflected in the complexity involved in assembling the molecular machines that carry out chromosomal DNA synthesis. Chapters by Ishino & Ishino and Martinez-Antonio et al. dis‐ cuss the process of DNA replication in bacteria and archaea and reveal aspects of the proc‐ ess that are conserved, and aspects that are unique when compared to eukaryotes.

The large size of eukaryotic chromosomes presents challenges to accomplishing accurate and timely DNA replication required for cell proliferation. The molecular machines that drive DNA unwinding and chromosomal DNA synthesis are assembled in a multi-step process that allows for many layers of potential regulation to ensure that DNA replication is initiated accurately and only when appropriate. Many of these mechanisms serve double duty to ensure that DNA replication is initiated only once in any given cell cycle. This is essential to ensure that all portions of the genome are replicated but that none are over-re‐ plicated which could lead to the formation of structures at risk for breakage or inappropriate recombination.

The assembly and activity of the DNA helicases and"replisome" that unwinds chromosomal DNA and drives DNA replication are reviewed and discussed in chapters by Stuart, Fisk et al., and Daniel, et al. The assembly of these fantastic DNA replication machines depends upon highly specific and exquisitely regulated protein-protein interactions achieved by spe‐ cific interaction domains and a subset of these important interaction domains and mecha‐ nisms are reviewed in chapters by Matthews & Guarne and Zavec.

The Integrity of chromosomal DNA replication is a high priority for cells and there are many mechanisms devoted to ensuring that damage to chromosomes is limited during the duplication processes. The intra S-phase checkpoint and mechanisms that retain integrity of the replication forks in the face of conditions that lead to pausing or stalling of the replica‐ tion process is discussed by Sabatinos & Forsburg who also present a model for the conse‐ quences of replication fork collapse during conditions when fork stalling or pausing occurs globally during the replication process. Cox & Mason describe the current state of under‐ standing of the WRN helicase that functions in mammalian cells with emphasis on the effect

of loss of function mutations in WRN that lead to Werners Syndrome, a disorder that reca‐ pitulates cellular aging.

Cellular DNA is not "naked" but is wrapped and folded into complex three-dimensional structures through its interaction with histone and other chromosomal proteins that com‐ prise chromatin. The histone proteins are subject to an array of post-translational modifica‐ tions that include acetylation, methylation, ubiquitination, and phosphorylation. The DNAprotein complex that is chromatin can exist in a range of structures varying in the degree of condensation and modification state of the proteins. Not surprisingly the state of the chro‐ matin has significant effects on the replication of the DNA, influencing the selection of start sites for DNA replication, the rate of fork progression and extent of fork pausing, as well as having effects on DNA repair and recombination. Chapters by Kubota et al., Aloui et al, Di Tomaso et al., Maya et al., and Galvani & Thiriet review aspects of the relationship of DNA replication to chromatin structure and epigenetic regulation.

Not all segments of chromosomal DNA are the same even within the same cell. Some re‐ gions of the chromosomes have unique characteristics required to carry out a particular function. The ends or telomeres of eukaryotic chromosomes are particularly interesting as they present a problem of how to fully replicate both strands without a loss of genetic information. The end replication problem and mechanisms that solve the problem are de‐ scribed in chapters by Grach and by Frydrychova and Mason.

This volume outlines and reviews the current state of knowledge on several key aspects of the DNA replication process. This is a critical process in both normal growth and develop‐ ment and in relation to a broad variety of pathological conditions including cancer. Under‐ standing and defining the molecular mechanisms that drive and regulate DNA replication will offer insight into the fundamental process that allows cellular life and proliferation. Ad‐ ditionally, these insights will ultimately offer the hope of controlling diseases like cancer that deregulate DAN replication and cell proliferation.

> **David Stuart** Associate Professor Department of Biochemistry University of Alberta Edmonton, Alberta Canada

**Machines that Drive DNA Replication**

of loss of function mutations in WRN that lead to Werners Syndrome, a disorder that reca‐

Cellular DNA is not "naked" but is wrapped and folded into complex three-dimensional structures through its interaction with histone and other chromosomal proteins that com‐ prise chromatin. The histone proteins are subject to an array of post-translational modifica‐ tions that include acetylation, methylation, ubiquitination, and phosphorylation. The DNAprotein complex that is chromatin can exist in a range of structures varying in the degree of condensation and modification state of the proteins. Not surprisingly the state of the chro‐ matin has significant effects on the replication of the DNA, influencing the selection of start sites for DNA replication, the rate of fork progression and extent of fork pausing, as well as having effects on DNA repair and recombination. Chapters by Kubota et al., Aloui et al, Di Tomaso et al., Maya et al., and Galvani & Thiriet review aspects of the relationship of DNA

Not all segments of chromosomal DNA are the same even within the same cell. Some re‐ gions of the chromosomes have unique characteristics required to carry out a particular function. The ends or telomeres of eukaryotic chromosomes are particularly interesting as they present a problem of how to fully replicate both strands without a loss of genetic information. The end replication problem and mechanisms that solve the problem are de‐

This volume outlines and reviews the current state of knowledge on several key aspects of the DNA replication process. This is a critical process in both normal growth and develop‐ ment and in relation to a broad variety of pathological conditions including cancer. Under‐ standing and defining the molecular mechanisms that drive and regulate DNA replication will offer insight into the fundamental process that allows cellular life and proliferation. Ad‐ ditionally, these insights will ultimately offer the hope of controlling diseases like cancer

> **David Stuart** Associate Professor

> > Canada

Department of Biochemistry

University of Alberta Edmonton, Alberta

replication to chromatin structure and epigenetic regulation.

scribed in chapters by Grach and by Frydrychova and Mason.

that deregulate DAN replication and cell proliferation.

pitulates cellular aging.

X Preface
