Homologous recombination

DNA damage, in the form of DNA double-strand breaks, poses a considerable threat to genomic integrity and cell survival. If left unrepaired, a single double-strand break is sufficient to cause cell death and, if repaired inappropriately, a double-strand break may give rise to a potentially oncogenic translocation. Double-strand breaks in genomic DNA may arise accidentally in a number of ways, including through exposure to harmful exogenous agents such as ionizing radiation or cytotoxic chemicals, as a consequence of mechanical stress, or through the breakdown of a replication fork. Alternatively, they may be introduced by endonucleases, as intermediates in normal cellular processes such as meiosis, or the mating type switch in yeast, or during V(D)J gene rearrangements in vertebrate T-cell development. The repair of double-strand breaks is so critical that eukaryotic organisms have developed two distinct mechanisms to deal with it. One mechanism involves the simple rejoining of the broken DNA ends, regardless of sequence, a process known as nonhomologous end joining. This mechanism has the major drawback that it is somewhat inaccurate, as small deletions may be introduced at the site of the DNA break. In the G1 phase of the cell cycle, however, when there is only one copy of each chromosome, the repair of double-strand breaks by nonhomologous end joining is crucial for cell survival. The second mechanism of double-strand break repair takes advantage of the fact that, in S-phase, DNA replication generates an identical copy of each DNA molecule. In this situation double-strand breaks may be repaired by using the undamaged copy of the DNA as a template, to restore the break in the damaged DNA without the loss of genetic information. This high-fidelity DNA repair mechanism is homologous recombination. Repair of double-strand breaks by homologous recombination not only helps protect cells against the potentially lethal effects of DNA damage but, in the process, helps generate the genetic diversity that drives evolution.