Maintenance Of The Genome

PART OUTLINE Chapter 6 Chapter 7

The Structures of DNA and RNA

Chromosomes, Chromatin, tind the Nucieosome

Chapter 8 The Replication of DNA

Chapter 9 The Mutability and Repair of DNA

Chapter 10 Homologous Recombination at the Moleculaf Level

Chapter 11 Site-Specific Recombination and Transposition of DNA

Part 2 is dedicated to the structure of DNA and the processes thai propagate, maintain, and ¿¡Iter it from cine cell generation to the next. In Chapters 6 through 11, we will examine DNA and its close relative, RNA, and address the following questions:

• How do the structures of DNA and RNA account for their functions?

• How are DNA molecules, which are extraprdinardy long compared to the size nf the cell, packaged within the nucleus?

• How is DNA replicated accurately and completely during the cell cycle, and how is this achieved with high fidelity?

• How is DNA protected from spontaneous and environmental damage, and how is damage, unce inflicted, reversed?

• How are DNA sequences exchanged between DNA chromosomes in processes known as recombination and transposition?

hi answering these questions, we will see that the DNA molecule is subject both to conservative processes that act to maintain it unaltered from generation to generation, and to other processes that bring abciut profound changes in the genetic material that help drive evolution. In the ceil, DNA is subjected to forces that peel apart its strands, twist it into topologically constrained structures, wrap it around and through protein assemblies, and break and reseal its backbone. These manipulations are mediated by myriad enzymes and molecular machines that propagate, maintain, and alter the genetic material.

Chapter G explores the structure of DNA in atomic detail, from the chemistry of its bases and backbone, to the base-pairing interactions and other forces that hold the two strands together. DNA is often topologically constrained, and Chapter 6 considers the biological effects of such constraints, together with enzymes that alter topology. This chapter also explores the structure of RNA. Despite the close similarity of its chemistry to that of DNA, RNA has its own distinctive structural features and properties, including the remarkable capacity to act as a catalyst in several cellular processes.

As we will learn in Chapter 7, DNA is not naked in the cell. Rather, it is packaged with specialized proteins in a structure called chromatin. This packaging allows exceedingly long molecules to be accommodated in the cell and to be accurately segregated to daughter cells during cell division. Chromatin can be modified to increase or decrease the accessibility of the DNA. These changes contribute to ensuring it is replicated, recombined, and transcribed at the right time and in the right place. Chapter 7 introduces us to the histone and nonhistone components of chromatin, to the structure of chromatin, and to the enzymes that mediate chromatin modification.

The structure of DNA offered a likely mechanism for how genetic material is duplicated. Chapter 8 describes this copying mechanism in detail, We describe the semiconservative nature of DNA replication, and the elaborate collection of enzymes and other proteins required to carry it out.

But the replication machinery is not infallible. Each round of replication results in errors, which, if left uncorrected, would become mutations in daughter DNA molecules. In addition, DNA is a fragile molecule that undergoes damage spontaneously and from chemicals and radiation. Such damage must be delected and mended if the genetic material is to avoid rapidly accumulating an unacceptable load of

Port 2 Maintenance of the Genome 35

mutations. Chapter 9 is devoted to the mechanisms that detect and repair damage in DNA. Organisms from bacteria to humans rely on similar, and often highly conserved, mechanisms for preserving the integrity of their DNA. Failure of these systems has catastrophic consequences, such as cancer.

The final two chapters of Pari 2 reveal a complementary aspect of ON A metabolism. In contrast to the conservative processes of replication and repair, which seek to preserve the genetic material with minimal alteration, the processes considered in these chapters are designed to bring about new arrangements of DNA sequences. Chapter 10 covers the topic of homologous recombination—the process of breakage and reunion by which very similar chromosomes (homologs) exchange equivalent segments of DNA. Homologous recombination allows tlie generation of genetic diversity, and also replacement of missing or damaged sequences. Two models for pathways of homologous recombination are described, as well as the fascinating set of molecular motors that search for homologous sequences between DNA molecules and then create and resolve the intermediates predicted by the pathway ntodels.

Finally, Chapter 11 brings us to two specialized kinds of recombination known as site-specific recombination and transposition. These processes lead to the vast accumulation of some sequences within the genomes of many organisms, including humans. We will discuss the molecular mechanisms and biological consequences of these forms of genetic exchange.

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