Damage to DNA is unavoidable and arises in many ways. DNA damage can be caused by spontaneous cleavage of chemical bonds in DNA, by environmental agents such as ultraviolet and ionizing radiation, and by reaction with genotoxic chemicals that are by-products of normal cellular metabolism or occur in the environment. A change in the normal DNA sequence, called a mutation, can occur during replication when a DNA polymerase inserts the wrong nucleotide as it reads a damaged template. Mutations also occur at a low frequency as the result of copying errors introduced by DNA polymerases when they replicate an undamaged template. If such mutations were left uncorrected, cells might accumulate so many mutations that they could no longer function properly. In addition, the DNA in germ cells might incur too many mutations for viable offspring to be formed. Thus the prevention of DNA sequence errors in all types of cells is important for their survival, and several cellular mechanisms for repairing damaged DNA and correcting sequence errors have evolved. One of these mechanisms for repairing breaks in double-stranded DNA is also used by eukaryotic cells to generate new combinations of maternal and paternal genes on each chromosome through the exchange of segments of the chromosomes during the production of germ cells (e.g., sperm and eggs), a process known as genetic recombination.

Significantly, defects in DNA repair mechanisms and cancer are closely related. When repair mechanisms are compromised, mutations accumulate in the cell’s DNA. If these mutations affect genes that are normally involved in the careful regulation of cell division, cells can begin to divide uncontrollably, leading to tumor formation and cancer. Chapter 24 outlines in detail how cancer arises from defects in DNA repair mechanisms. We will encounter a few examples in this section as well as we first consider the ways in which DNA integrity can be compromised, then discuss the repair mechanisms that cells have evolved to ensure the fidelity of this very important molecule.