INTRODUCTION

This chapter provides a basic description of the major biochemical pathways that operate in mammalian cells to maintain the structure and integrity of genomic DNA. This is no trivial task for multicellular organisms, since, as we shall see, they are continually exposed to a plethora of agents that cause DNA damage. Failure to repair damaged DNA efficiently and consistently is incompatible with cellular life as we know it, and a large number of severe clinical disorders can now be attributed to defects in the cellular DNA repair machinery. We will look at examples of these in a little more detail below.

The importance of this vital function is further illustrated by the fact that DNA repair mechanisms are, for the large part, functionally conserved from primitive prokaryotes through to higher-order eukaryotes such as humans. Furthermore, at the time of writing (2006), over 150 gene products had been identified in humans that appear to have evolved primarily as either structural or catalytic components of DNA repair pathways, or gatekeepers of various stages of the cell cycle that are deliberately manipulated when DNA repair pathways are invoked. Readers are encouraged to consult an interesting web resource that has been constructed to describe the growing list of DNA repair genes at www.cgal.icnet.uk/ DNA_Repair_Genes.html

THE SPECTRUM OF DNA DAMAGE

For many years molecular biologists described DNA as a highly stable component of the cellular machinery that changes very little in structure or chemistry over time. The well established fact that DNA is the repository of coding information for all cellular life, and is responsible for the inheritance of this information from generation to generation, suggested that inherent physicochemical properties of DNA rendered it essentially chemically immutable. Recent evidence, however, has revealed a vastly different scenario, one in which all organisms are constantly exposed to a plethora of agents that cause significant structural and chemical changes in their DNA. Moreover, these changes are now known to occur through ongoing inter actions between DNA and by-products of normal cellular metabolism.