DNA double-strand break repair

The integrity of genomic DNA is crucial for its function. And yet, DNA in living cells is inherently unstable. It is subject to mechanical stress and to many types of chemical modification that may lead to breaks in one or both strands of the double helix. Within the cell, reactive oxygen species generated by normal respiratory metabolism can cause double-strand breaks, as can stalled DNA replication. External agents that cause double-strand breaks include ionizing radiation and certain chemotherapeutic drugs. DNA double-strand breaks are also made and repaired during meiosis when recombination takes place between paired homologous chromosomes, during the rearrangement of immunoglobulin gene segments in lymphocyte development and during integration of certain mobile genetic elements and viruses into the host cell DNA. It is difficult to know how often double-strand breaks occur in the genome of a cell not exposed to external DNA-damaging agents, but we know from work with yeast cells that one persistent DNA double-strand break can be sufficient to trigger the death of a cell. If double-strand breaks go unrepaired in mammalian cells, they can also cause gene deletion, chromosome loss and other chromosomal aberrations that might ultimately produce cancers. DNA double-strand breaks are repaired by means of two main mechanisms: nonhomologous end joining and homologous recombination (see Figure 1). Both mechanisms operate in all eukaryotic cells that have been examined but the relative contribution of each mechanism varies. For example, most mammalian cells seem to favour nonhomologous end joining (also called ‘illegitimate recombination’), whereas homologous recombination is more common in the budding yeast Saccharomyces cerevisiae. One possible reason for this difference might be the prevalence in mammalian cells of repetitive sequences, which could lead to gene amplification or deletion if homologous recombination were common. In addition to these main mechanisms, DNA double-strand breaks can be repaired by means of single-strand annealing between adjacent repeated DNA sequences, which involves deletion of the intervening DNA (see Figure 1). This article focuses mainly on nonhomologous end joining, the best-characterized mammalian DNA double-strand break repair mechanism.