Roles of DNA Polymerases in Replication, Repair, and Recombination in Eukaryotes

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The functioning of the eukaryotic genome depends on efficient and accurate DNA replication and repair. The process of replication is complicated by the ongoing decomposition of DNA and damage of the genome by endogenous and exogenous factors. DNA damage can alter base coding potential resulting in mutations, or block DNA replication, which can lead to double‐strand breaks (DSB) and to subsequent chromosome loss. Replication is coordinated with DNA repair systems that operate in cells to remove or tolerate DNA lesions. DNA polymerases can serve as sensors in the cell cycle checkpoint pathways that delay cell division until damaged DNA is repaired and replication is completed. Eukaryotic DNA template‐dependent DNA polymerases have different properties adapted to perform an amazingly wide spectrum of DNA transactions. In this review, we discuss the structure, the mechanism, and the evolutionary relationships of DNA polymerases and their possible functions in the replication of intact and damaged chromosomes, DNA damage repair, and recombination.

Introduction

DNA replication is one of the most fundamental processes in biology. It is required for the proper transmission of genetic information. Accurate and efficient replication and repair of genomic DNA are the bases for the evolutionary determined level of conservation of the genetic information and the prevention of genetic diseases (Bielas and Loeb, 2005, Friedberg et al., 2002, Kondo 1973, Loeb et al., 1974, Radman 1999).

The mechanism of replication is a polynucleotide template‐directed polymerization of deoxynucleoside triphosphates by a DNA polymerase using a “two‐metal‐ion” mechanism (Kornberg and Baker, 1991, Steitz 1998). The synthesis occurs exclusively in a 5′ to 3′ direction. Therefore, the two antiparallel strands of DNA duplexes should be replicated by somewhat different machineries (Garg and Burgers, 2005b, McHenry 2003). The current model postulates that the leading strand is synthesized continuously, whereas the lagging strand is synthesized in short patches that are sealed together by DNA ligase (Garg and Burgers, 2005b, Johnson and O'Donnell, 2005).

In addition to the replication of undamaged DNA, DNA polymerases are also involved in the replication and repair of damaged DNA. They participate in various excision repair pathways, in recombination repair, or in bypassing the blocking adducts, thus forming a network of proteins that acts sequentially in the maintenance of genome integrity (Budd et al., 2005, Stauffer and Chazin, 2004). A wide diversity of DNA substrates in various DNA transactions are used by DNA polymerases belonging to several structural families. This review summarizes the current knowledge about the roles of different DNA polymerases in DNA replication, repair, and recombination. We focus on DNA template‐dependent DNA polymerases, omitting terminal transferases, reverse transcriptases, telomerases, and RNA polymerases, which are reviewed extensively elsewhere (Benedict et al., 2000, Boeger et al., 2005, Collins 1996, Cramer 2004, Kelleher et al., 2002, Lingner and Cech, 1998, Ren and Stammers, 2005).

Here we are unable to cover the immerse literature in the field and will focus on the main functions of DNA polymerases. During the past 3 years, excellent reviews on various aspects of DNA polymerases appeared: on replisome assembly (Johnson and O'Donnell, 2005), on polymerases at the fork (Garg and Burgers, 2005b), on the general functions of DNA polymerases (Bebenek and Kunkel, 2004) and their mechanisms related to structure (Rothwell and Waksman, 2005), on the mechanisms of translesion DNA synthesis (Prakash et al., 2005), on the structure of translesion DNA polymerases (Yang, 2005), on the mechanisms of polymerase switch (Friedberg 2005, Friedberg et al., 2005, Ulrich 2005b), on DNA polymerase fidelity (Kunkel, 2004), on the regulation of DNA replication through the S phase (Takeda and Dutta, 2005), on replication complexes in genome stability (Toueille and Hubscher, 2004), and many others. We cite only cornerstone experimental papers and most frequently refer the reader to recent reviews.

Section snippets

Overview of the Maintenance of Genome Stability

The bases in cellular DNA are continuously damaged by spontaneous hydrolysis and oxidation and other endogenous and environmental mutagens (Table I). The mutation rate in mammals, however, is kept low with one mutation or less per effective genome per sexual generation (Drake, 1999). Accurate and efficient replication and repair processes have evolved to achieve this goal. Most of these processes include DNA synthesis by DNA polymerases (Fig. 1). Intact DNA molecules are replicated with high

Fidelity of DNA Polymerases on Undamaged and Damaged Templates

The key characteristic of DNA polymerases important for the proper transmission of the genetic information is the fidelity. The accuracy of DNA synthesis by eukaryotic template‐dependent DNA polymerases varies six orders of magnitude (Section III.B.1). Members of the A and B families, with a few exceptions, are among the most accurate polymerases, while the Y family polymerases are the least accurate. In the sections below, we review the methods of measuring the fidelity of DNA polymerases and

Polymerases Involved in the Reduplication of Genomes

In this section we describe the polymerases whose function is indispensable for life or the proper function of organelles.

Human Diseases Caused by Aberrant Replication

Genome stability can be compromised not only by DNA damage. Some DNA sequence contexts can impede DNA replication or repair. A classical example of genomic instability caused by problems in replicating an unusual DNA template is repeat expansions. These so‐called “dynamic mutations” are the cause of more than 40 human disorders with a wide range of manifestations, such as mental retardation, muscular atrophy, cranial dysplasia, and increased risk of prostate cancer (Pearson et al., 2005). The

Conclusions and Future Perspectives

Despite the multiple gaps in our knowledge, the extensive growth of DNA polymerase families in recent years made a significant contribution to our understanding of the mechanism of DNA replication and repair. We predict that in the upcoming years the mechanisms of regulation and interaction of DNA polymerases during various types of DNA synthesis will be revealed. We anticipate that the borders between functional classes of replicative, repair, and TLS polymerases will become more and more

Acknowledgments

We thank Kasia Bebenek and Tadayoshi Bessho for critically reading the manuscript. We are grateful to Francisco Asturias, Kasia Bebenek, Luis Blanco, Peter Burgers, Miguel Garcia‐Diaz, Myron Goodman, Peter Gruz, Erik Johansson, Cathy Joyce, Tom Kunkel, Andrei Kuzminov, Matt Longley, Hisaji Maki, Alex Mazin, Sergei Mirkin, Linda Reha‐Krantz, Elli Rogan, Evelyne Sage, Motoshi Suzuki, Zhigang Wang, Roger Woodgate, and Wei Yang for discussions of various aspects of DNA polymerases during the course

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