Other critical repair systems—based on either nonhomologous end joining or homologous recombination—reseal the accidental double-strand breaks that occur in the DNA helix. In most cells, an elevated level of DNA damage causes a delay in the cell cycle, which ensures that DNA damage is repaired before a cell divides.
In the two preceding sections, we discussed the mechanisms that allow the DNA sequences in cells to be maintained from generation to generation with very little change. In this section, we further explore one of the DNA repair mechanisms, a diverse set of reactions known collectively as homologous recombination. The key feature of homologous recombination (also known as general recombination) is an exchange of DNA strands between a pair of homologous duplex DNA sequences, that is, segments of double helix that are very similar or identical in nucleotide sequence. This exchange allows one stretch of duplex DNA to act as a template to restore lost or damaged information on a second stretch of duplex DNA. Because the template for repair is not limited to the strand complementary to that containing the damage, homologous recombination can repair many types of DNA damage. It is, for example, the main way to accurately repair double-strand breaks, as introduced in the previous section (see Figure 5–45B). Double-strand breaks can result from radiation and reactive chemicals, but most of the time they arise from DNA replication forks that become stalled or broken independently of any such external cause. Homologous recombination accurately corrects these accidents and, because they occur during nearly every round of DNA replication, this repair mechanism is essential for every proliferating cell. Homologous recombination is perhaps the most versatile DNA repair mechanism available to the cell; the “all-purpose” nature of recombinational repair probably explains why its mechanism and the proteins that carry it out have been conserved in virtually all cells on Earth.
Additionally, we shall see that homologous recombination plays a special role in sexually reproducing organisms. During meiosis, a key step in gamete (sperm and egg) production, it catalyzes the orderly exchange of bits of genetic information between corresponding (homologous) maternal and paternal chromosomes to create new combinations of DNA sequences in the chromosomes passed to the offspring.
The current view of homologous recombination as a critical DNA repair mechanism in all cells evolved slowly from its original discovery as a key component in the specialized process of meiosis in plants and animals. The subsequent recognition that homologous recombination also occurs in unicellular organisms made it much more amenable to molecular analyses. Thus, most of what we know about the biochemistry of genetic recombination was originally derived from studies of bacteria, especially of E. coli and its viruses, as well as from experiments with simple eukaryotes such as yeasts. For these organisms with short generation times and relatively small genomes, it was possible to isolate a large set of mutants with defects in their recombination processes. The protein altered in each mutant was then identified and, ultimately, studied biochemically. Close relatives of these proteins have been found in more complex eukaryotes including flies, mice, and humans, and more recently, it has been possible to directly analyze homologous recombination in these species as well. These studies reveal that the fundamental processes that catalyze homologous recombination are common to all cells.
The hallmark of homologous recombination is that it takes place only between DNA duplexes that have extensive regions of sequence similarity (homology). Not surprisingly, base-pairing underlies this requirement, and two DNA duplexes that are undergoing homologous recombination “sample” each other’s DNA sequence by engaging in extensive base-pairing between a single strand from one DNA duplex and the complementary single strand from the other. The match need not be perfect, but it must be very close for homologous recombination to succeed.